HCV infection is a worldwide common health problem having a high affinity for long persistent infections which may develop to considerable changes in liver like hepatocellular carcinoma, cirrhosis and chronic hepatitis. HCV is inherently unstable, giving rise to multiple genotypes and more than 50 subtypes. Mutations that occur during viral replications result in its substantial heterogeneity and overtime in one entity multiple dozen mutant strains may be found. Due to geographical distribution of several different genotypes of Hepatitis C Virus in the world, many of them giving out multiple routes of infection. Constant response to treatment of HCV genotype is a burly forecaster. Assessment of rating and phase is used in evaluating histological outcome in clinical trials or as variables in statistical analyses of progression or therapeutic response. Beginning of amalgamation treatment with ribavirin and interferon has deliberately enhanced clinical result. The achievement of these treatments may be measured in conditions of biochemical comeback and virohistological response. Keeping the above facts in observation the current research is planned to find out the genotyping of HCV RNA causing persistent hepatitis in interior Sindh and to investigate its association with mode of transmission, histological staging and grading, threat and response to therapy. This multi centric study was conducted at Research Medical Centre of LUMHS Jamshoro, Pathology Department of PUMHS Nawabshah and Biotechnology Department of Karachi University, during August 2006 to December 2009. Blood samples of 344 (239 male and 105 female) patients were collected from medical wards of PUMHC Hospital, LUMHS Hospital, CMC Hospital Larkana, and Muhammadi Medical College Hospital Mirpurkhas to cover the population of the whole the interior Sindh. The suspected patients were informed about the study and who also signed a consent form. ELISA for the presence of HCV antibodies was performed and positive patients were submitted to a laboratorial protocol. The clinical and epidemiological data were recorded on a proforma and various biochemical tests were performed. HCV RNA was detected by RT PCR (Quantitative and Qualitative methods), the first viral load was low in 295 (85.96%) cases, medium in 29 (8.43%) cases, high in 15 (4.36%) and very high in 5 (1.45%) cases. The genotying was performed and the results of genotyping revealed that HCV 3a was the major genotype in 242(70.34%) cases, followed by genotype 3b in 19(5.52%) cases, genotype 1a in 10(2.61%) cases, genotype 1b in 5(1.45%) cases, genotype 2 in 4(1.16%) cases, genotype 5 in 3(0.87%) cases and mixed genotype in 9(2.61%) cases. However no other genotype could be identified in 52(15.11%) cases and hence were considered as “untypable”. Determining the risk factor, majority of the patients 135(39.24%) had parental history of multiple use of needles/syringes followed by minor/major surgery in 64(18.60%) cases and dental procedures, transfusion of blood and blood products in 50(14.53%) cases, needle accidents in 34(9.88%) cases, history of nail clippers, tooth brushes shaving razors, and piercing instruments in 35 (10.17%) patients, 10(2.9%) cases had promiscuous sex act history, I/V drug users in 8(2.32%), and tattoo marks in 3(0.78%) cases. The commonest route of transmission in genotype 1a and 1b (60%) was major/minor surgery, each followed by multiple use of needles/syringes; needle accidents and IV drug use. While the commonest route of transmission in genotype 3a, 3b, 2, 5, mixed and untypable was multiple use of needles and syringes followed from the past blood products, transfusion of blood, surgery, history of shaving of razors etc, I/V drug use promiscuous sexual practice (act) and tattoo marks. Histopathological analysis indicates 38(11.04%) cases in grade A1, 151(43.89%) in A2, 117(34.01%) in A3 and 38(11.04%) cases in A4 and no case in A0. Fibrosis seen in stage F2 and F1 in 121(35.17%) and 102(29.65%), followed by F3, F4 and F0. In correlation with genotypes most of the cases of 1a and 1b fall into A3, A4,F3 and F4, while most of cases of genotype 3a, 3b, 2, 5 fall in A1, A2,A3,F1 and F2. The response to combined 6-12 months (depending upon genotype) therapy, 276(80.23%) cases showed positive response, while 68(19.76%) showed no response which include 1a, 1b, 3a, mixed and untypable genotypes mostly with high and very high viral load cases. The sustained response to combined therapy showed that 276(80.23%) had positive response after 6-12 months of combined therapy, while 214 (62.20%) cases had sustained response after 6 months of stopping the combined therapy. Out of 276 cases of positive response with combined antiviral therapy, 272 (98.55%) cases showed low level of initial viral load, while out of 68 unresponsive 48 (66.1%) showed medium, high and very high level initial viral load. The current study verifies the results of various international researches; this is the first ever study conducted which covers the data of the whole interior Sindh. The information gained out of the current study will help improving our understanding of HCV which will be beneficial for clinicians in treating these patients with precise therapy. Furthermore, investigating the association of genotype with histological staging and grading, threat and response to treatment will also show its impact on progression of persistent hepatitis C and curing stratigies. Key Words: HCV RNA, Chronic hepatitis, Genotyping, Transmission, Histological staging and grading, Treatment response.