Regulator of G protein signaling (RGS) proteins are responsible for the rapid turnoff of G protein-coupled receptor signaling pathways. RGS9‑2, a brain‑specific splice variant of the RGS9 gene, is highly expressed in the striatum but lowly expressed in the periaqueductal gray and spinal cord, which mediate various actions of morphine and other opiates. In order to identify the markers that contribute to the genetic susceptibility of heroin dependence, the potential association between heroin dependence and 10 single nucleotide polymorphisms (SNPs), including rs8077696, rs8070231, rs2292593, rs2292592, rs9916525, rs1122079, rs4790953, rs1530351, rs4791230 and rs2869577 of the RGS9 gene was evaluated using the MassARRAY system. The present study recruited 425 heroin‑dependent patients and 205 healthy controls. The results revealed that two SNPs (rs1530351 and rs4791230) located in the promoter region of the RGS9 gene, were significantly associated with heroin dependence (P<0.05). The frequency of the C allele in rs1530351 (χ2=8.031, P=0.005, OR=2.079, 95% CI=1.241‑3.483) and the G allele in rs4791230 (χ2=7.360, P=0.007, OR=2.021, 95% CI=1.205‑3.389) in the heroin‑dependent patients was significantly higher than that in the controls. Furthermore, linkage disequilibrium was observed in three blocks (D'>0.9) and significantly less T‑A haplotypes (χ2=4.867, P=0.027, OR=0.442, 95% CI=0.210‑0.929) were identified in the heroin‑dependent patients, suggesting that they may exhibit protective effects against heroin dependence. These findings indicate a role for RGS9 gene polymorphisms in heroin dependence and may be informative for future genetic or biological studies on heroin dependence.