Prodynorphin (PDYN) binds to kappa-opioid receptors and is known to regulate dopaminergic tone, making this system important for the reinforcing and rewarding properties of drugs of abuse such as opioids. The binding of dynorphins to kappa-opioid receptors also produces aversive states that may affect the development of opioid dependence. Recent animal results have shown that PDYNknockout mice show decreased ethanol consumption; however, this finding was restricted to female mice. We were interested to analyse a possible gender specificity of dynorphin effects in humans and to this end three single-nucleotide polymorphisms (SNPs) in PDYN were genotyped in a Chinese population of 484 opioid dependents and 374 controls. An interaction between sex and genotype was found in female opioid dependents. Chi-squared tests for association revealed that the genotype distributions of SNPs rs1997794 (P = 0.019) and rs1022563 (P = 0.006) in the promoter and 3' region of PDYN, respectively, were found to be associated with opioid dependence. Therefore, SNPs in PDYN are significantly associated with the risk of developing opioid dependence; however, this effect may only be seen in females. These data suggest that PDYN polymorphisms should be studied in additional female opioid-dependent populations with an emphasis on the promoter and 3' regions of the gene.