Early life stress (ELS) can induce long-term changes of brain functions and behavior, thus representing a significant risk factor for the development of mental disorders such as depression and anxiety. A brain system particularly affected by ELS is the endocannabinoid system, a critical regulator of socio-emotional behavior and the stress response. In a first study we showed that adult female rats exposed to ELS show significant changes in their behavioural phenotype, specifically depressive-like symptoms such as anhedonia and disturbed social behavior. These behavioral changes where paralleled by increased CB1R (cannabinoid-receptor-1) expression in the medial prefrontal cortex (mPFC) that were correlated with epigenetic modifications, specifically alterations in DNA-methylation at the CB1R-promoter. In a follow up study we tested whether ELS-induced effects are sex-specific. Thus, we analyzed if (i) adult male rats exposed to ELS develop pathological behavioral phenotypes; (ii) the proposed behavioral changes are paralleled by alterations in the CB1R expression in the mPFC; (iii) the predicted changes in CB1R gene expression are epigenetically regulated. Our results reveal that ELS induced a similar depressive-like phenotype in male rats as described for females. However, in contrast to our findings in females, ELS males showed decreased CB1R gene expression in the mPFC and no change in DNA-methylation. Instead, reduced acetylation of histone 3 was observed in ELS males. Our results indicate that ELS affects the endocannabinoid system in the mPFC of male and female rats in an opposite direction and that these effects are at least partly mediated by sex-specific epigenetic modifications.