Gall bladder cancer (GBC) is a gastro-intestinal cancer with high prevalence among north Indian women.Platelet derived growth factor-B (PDGFB) and human epidermal growth factor receptor-2 (HER2) may playroles in the etiology of GBC through the inflammation-hyperplasia-dysplasia-carcinoma pathway. To study theassociation of PDGFB and HER2 polymorphisms with risk of GBC, 200 cases and 300 controls were considered.PDGFB +286A>G and +1135A>C polymorphisms were investigated with an amplification refractory mutationsystem and the HER2 Ile655Val polymorphism by restriction fragment length polymorphism. Significant riskassociations for PDGFB +286 GG (OR=5.25) and PDGFB +1135 CC (OR=3.19) genotypes were observed forGBC. Gender wise stratification revealed susceptibility for recessive models of PDGFB +1135A>C (OR=3.00) andHER2 Ile655Val (OR=2.52) polymorphisms among female GBC cases. GBC cases with gall stones were predisposedto homozygous +286 GG and +1135 CC genotypes. Significant risk associations were found for ACIle (OR=1.48),GAVal (OR=1.70), GAIle (OR=2.00) haplotypes with GBC cases and GCIle haplotype with female GBC cases(OR=10.37, P=<0.0001). Pair-wise linkage disequilibrium revealed negative associations among variant alleles.On multi-dimensional reduction analysis, a three factor model revealed significant gene-gene interaction forPDGFB +286A>G, PDGFB +1135A>C and HER2 Ile165Val SNPs with GBC. Protein-protein interaction showedsignificant association of PDGFB and HER2 with the epidermal growth factor receptor signaling pathway.