Background & Aims: Adenosine diphosphate ribosyl transferase (ADPRT) and x-ray repair cross-complementing 1 (XRCC1) are major DNA base excision repair proteins acting interactively in repair processes. This study examined the effects of ADPRT Val762Ala and XRCC1 Arg399Gln polymorphisms on ADPRT-XRCC1 interaction in vitro in cells and their contributions to gastric cardia adenocarcinoma (GCA) risk. Methods: The ADPRT-XRCC1 interaction in cells transfected with ADPRT and XRCC1 variant complementary DNA (cDNA) constructs were examined by immunoprecipitation and immunoblotting analysis. Genotypes were analyzed in 500 patients and 1000 controls, and odds ratios (ORs) were estimated by logistic regression. Results: Interactions between ADPRT-762Val and XRCC1-399Arg or XRCC1-399Gln were robust, but interactions between ADPRT-762Ala and either XRCC1-399Arg or XRCC1-399Gln were very weak. A case-control analysis showed ORs of 2.17 (95% CI, 1.55–3.04) and 1.61 (95% CI, 1.06–2.44) for GCA in the ADPRT Ala/Ala or XRCC1 Gln/Gln genotype carriers, respectively, compared with noncarriers. Gene-gene interaction of ADPRT and XRCC1 polymorphisms increased the OR of GCA in a multiplicative manner (OR for the presence of both ADPRT Ala/Ala and XRCC1 Gln/Gln genotypes, 6.43; 95% CI, 1.80–22.97). A supermultiplicative joint effect between the ADPRT polymorphism and smoking was observed. The ORs (95% CIs) of the Ala/Ala genotype for nonsmokers and smokers who smoked ≤24 or >24 pack-years were 1.44 (0.89–2.32), 2.00 (1.09–3.67), or 3.19 (1.59–6.42), respectively ( P trend test = .008). Conclusions: The ADPRT and XRCC1 polymorphisms confer host susceptibility to GCA, which might result from reduced ADPRT-XRCC1 interaction and attenuated base excision repair capacity.