Post-traumatic stress disorder (PTSD) is a psychiatric syndrome that occurs after trauma exposure. Neurotransmitters such as dopamine and oxytocin have been reported to be involved in neuropathology of PTSD. Previous studies indicated that the dopamine-oxytocin interaction may contribute to behavioral disorders. Thus, exploring the epistasis (gene-gene interaction) between oxytocinergic and dopaminergic systems might be useful to reveal the genetic basis of PTSD. In this study, we analyzed two functional single nucleotide polymorphisms (SNPs), rs2268498 for oxytocinergic gene OXTR and rs1801028 for dopaminergic gene DRD2 based on putative oxytocin receptor-dopamine receptor D2 (OTR-DR2) heterocomplex in a Chinese cohort exposed to the 2008 Wenchuan earthquake (156 PTSD cases and 978 controls). Statistical analyses did not find any single variant or gene-environment interaction (SNP x earthquake-related trauma exposure) associated with provisional PTSD diagnosis or symptoms. An OXTR-DRD2 interaction (rs2268498 x rs1801028) was identified to confer risk of provisional PTSD diagnosis (OR= 9.18, 95%Cl = 3.07-27.46 and P= 7.37e-05) and further subset analysis indicated that rs2268498 genotypes controlled the association directions of rs1801028 and rs1801028 genotypes also controlled the association directions of rs2268498. Rs2268498 x rs1801028 is also associated with PTSD symptoms (P= 0.043). Our study uncovered a genetic and putative function-based contribution of dopaminergic-oxytocinergic system interaction to PTSD.