Caspase-8 (CASP8) is a key controller of apoptosis, and its deregulation plays an important role in carcinogenesis. To evaluate the role of CASP8 polymorphisms in gallbladder cancer (GBC), we examined the risk associated with three single-nucleotide polymorphisms (SNPs) in a case-control study in North Indian population. Genotypes and haplotypes of the CASP8 polymorphisms (-652 6N ins/del; rs3834129, Ex13 + 51G > C; rs1045485 and IVS12-19 G > A; rs3769818) were determined for 230 GBC patients and 230 cancer-free controls randomly selected from the population. Odds ratio (OR) and 95% confidence interval (95% CI) were calculated in multivariate logistic regression analysis for the association of individual SNPs and haplotypes with GBC. Carriers for the "del" allele of rs3834129 SNP were associated with a 0.60-fold decreased risk for GBC (95% CI = 0.42-0.88; P(trend) = 0.005). In the combined analysis of the three CASP8 variants, we found that the individuals with the diplotypes carrying two copies of the common CASP8 del-G-G haplotype had 0.35-fold reduced risk (95% CI = 0.14-0.85) when compared with the diplotype containing 0-1 copy. The false-positive report probability (FPRP) approach advocated that these results were noteworthy (FPRP < 0.5). The molecular modeling results of rs1045485 polymorphism indicated that the overall configuration of both wild-type and polymorphic CASP8 protein were similar, with negligible deviation at the site of the polymorphism itself. In summary, low penetrance variants in CASP8 gene may alter the susceptibility toward GBC.