The present study searched for replicable risk genomic regions for alcohol and nicotine co‐dependence using a genome‐wide association strategy. The data contained a total of 3,143 subjects including 818 European‐American (EA) cases with alcohol and nicotine co‐dependence, 1,396 EA controls, 449 African‐American (AA) cases, and 480 AA controls. We performed separate genome‐wide association analyses in EAs and AAs and a meta‐analysis to derive combined P‐values, and calculated the genome‐wide false discovery rate (FDR) for each SNP. Regions with P < 5 × 10−7 together with FDR < 0.05 in the meta‐analysis were examined to detect all replicable risk SNPs across EAs, AAs, and meta‐analysis. These SNPs were followed with a series of functional expression quantitative trait locus (eQTL) analyses. We found a unique genome‐wide significant gene region—SH3BP5‐NR2C2—that was enriched with 11 replicable risk SNPs for alcohol and nicotine co‐dependence. The distributions of −log(P) values for all SNP‐disease associations within this region were consistent across EAs, AAs, and meta‐analysis (0.315 ≤ r ≤ 0.868; 8.1 × 10−52 ≤ P ≤ 3.6 × 10−5). In the meta‐analysis, this region was the only association peak throughout chromosome 3 at P < 0.0001. All replicable risk markers available for eQTL analysis had nominal cis‐ and trans‐acting regulatory effects on gene expression. The transcript expression of the genes in this region was regulated partly by several nicotine dependence (ND)‐related genes and significantly correlated with transcript expression of many alcohol dependence‐ and ND‐related genes. We concluded that the SH3BP5‐NR2C2 region on Chromosome 3 might harbor causal loci for alcohol and nicotine co‐dependence. © 2012 Wiley Periodicals, Inc.