Accumulating data suggest that CB2 receptor plays a crucial role in development of anxiety via regulatory function of stress response and neuroimmune crosstalk. Although animal experiments confirm this relationship, relevant human genetic studies on CB2 receptor gene (CNR2) in association with affective phenotype are absent.CNR2 R63Q and FAAH C385A functional polymorphisms were genotyped of 921 volunteers from the general population. Phenotypic variables were measured by the Zung Self-related Depression Scale (ZSDS), The State-Trait Anxiety Inventory (Trait subscale, STAI-T) and the depressive and anxious subscales of the Brief Symptom Inventory (BSI-DEP and BSI-ANX). Early life trauma was assesssed by the Childhood Trauma Questionnaire (CHQ). Using general linear models we tested possible associations between phenotypic variance and genotype distribution.There was a significant main effect of RR genotype of R63Q on ZSDS score (p = 0.007) and a remarkble interacting effect of CHQ and R63Q on scores of ZSDS, STAI-T and BSI-ANX scales (p = 0.009; p = 0.003; p = 0.001; respectively). R allele of R63Q and A allele of FAAH C385A were associated with significantly higher ZSDS, STAI-T and BSI-ANX scores compared to non-risk allele carriers (p = 0.009; p = 0.007; p = 0.007, respectively). The highest phenotypic scores were observed in GxGxE model (pZSDS = 0.04; pBSI-DEP = 0.006; pSTAI-T = 0.001; pBSI-ANX = 3.8 × 10-5).In this first human genetic study on CNR2 and childhood trauma we revealed that dysfunctional CB2 receptor and FAAH can contribute to greater sensitivity for childhood trauma possibly via weaker inhibiton of inflammatory and overactivated HPA axis.