There are a growing number of studies conducted in different parts of the world to understand the genetic etiology of urinary bladder cancer (UBC), which is a life- threatening disorder. Therefore to find the susceptible genetic loci we conducted a case-control genetic association study on Pakistani urothelial carcinoma patients (N = 200) and healthy controls (N = 200). For this purpose, four types of sequence variations were studied viz. VNTR polymorphism of eNOS, Alu repeat variation of ACE gene, null polymorphisms of GSTT and GSTM genes and selected common variants of GSTP1, MTHFR, PSCA, TNFα, p21, TP53, CYP1B1, XPD, XRCC1, CAV1, PON1, IGFBP3, VEGFA, LEP, LEPR, PPARγ genes as well as intergenic 8q24 region. In addition to an overall risk assessment, these polymorphisms were also analyzed with respect to the smoking status as well as with respect to tumor grade and stage. Haplotype-based association analysis of variants residing in linkage disequilibrium were also carried out and a gene-gene interaction was studied with reference to combined genotype analysis of functionally related genes. The risk variants of GSTM, LEPR, ACE, PSCA and 8q24.21 locus (rs9642880 and rs6983267) were found to be associated with significantly higher risk while IGFBP3 variant and haplotypes of CAV1 and MTHFR were found to be associated with reduced risk of UBC in the overall comparison of cases and controls. In the gene-smoking interaction CYP1B1, p21 (Ser allele), ACE and rs9642880 conferred a high UBC risk in smokers while LEPR and PSCA variants were found to be associated with increased risk of bladder oncogenesis in non-smokers only. In addition, p21 (Arg allele) was found to be associated with reduced UBC susceptibility in smokers while IGFBP3 and CAV1 haplotypes protected against urothelial carcinoma of the bladder in non-smokers only. GSTM0 and the risk allele of rs6983267 did not show a gene-smoking interaction because of their significant risk contribution in both smoker and non-smoker groups. With reference to tumor grade and stage, a trend of similar genetic etiologies was observed in low grade and non-invasive tumor, while the high grade and invasive tumor types were also found to have common genetic etiologies which were different from the former group. GSTM0, LEPR and rs9642880 were found to be associated with enhanced risk of low grade as well as non-invasive bladder carcinoma. GSTT0, CAV1, PSCA and PPARγ were found to predispose individuals to an elevated risk of ixhigh grade and invasive tumor. ACE and rs6983267 were non-specifically associated with both low and high grades as well as with non-invasive and invasive tumors. IGFBP3 SNP protected against low and high grade as well as against non-invasive stage. The haplotypes of MTHFR were found to confer a high risk of non-invasive tumor while providing protection against MIBC. In brief, the present study revealed the association of some of the genetic variants to the overall disease susceptibility in addition to some gene-smoking and gene-gene interactions.