There is evidence that dopamine receptors D2 (DRD2) and D4 (DRD4) polymorphisms may influence substance use disorders (SUD) susceptibility both individually and through their influence in the formation of DRD2\u2013DRD4 heteromers. The dopaminergic role on the vulnerability to addiction appears to be influenced by sex. A cross-sectional study with 307 crack cocaine addicts and 770 controls was conducted. The influence of\u00a0DRD2\u00a0rs2283265 and\u00a0DRD4\u00a048\u00a0bp VNTR in exon 3 variants, as well as their interaction on crack cocaine addiction susceptibility and severity were evaluated in women and men separately. An association between the\u00a0DRD2\u00a0T allele and crack cocaine addiction was found in women. In this same group, interaction analysis demonstrated that the presence of\u00a0DRD2-T allele and concomitant absence of\u00a0DRD4-7R allele were associated with risk for crack cocaine addiction. No influence of\u00a0DRD2\u00a0and\u00a0DRD4\u00a0variants was observed in men regarding addiction severity. This study reinforces the role of dopaminergic genes in externalizing behaviors, especially the influence of DRD2\u2013DRD4 interaction on SUD. This is the fourth sample that independently associated the DRD2\u2013DRD4 interaction with SUD itself or related disorders. In addition, our findings point out to a potential difference of dopaminergic neurotransmission across sex influencing addiction susceptibility.<\/p>\n\n\n\n