The serotonin system has been suggested to moderate the association between childhood maltreatment and rumination, with the latter in its turn reported to be a mediator in the depressogenic effect of childhood maltreatment. Therefore, we investigated whether the associations of two epigenetic regulatory polymorphisms in the HTR2A serotonin receptor gene with Ruminative Responses Scale rumination and its two subtypes, brooding and reflection, are moderated by childhood adversity (derived from the Childhood Trauma Questionnaire) among 1,501 European white adults. We tested post hoc whether the significant associations are due to depression. We also tested the replicability of the significant results within the two subsamples of Budapest and Manchester. We revealed two significant models: both the association of methylation site rs6311 with rumination and that of miRNA binding site rs3125 (supposed to bind miR-1270, miR-1304, miR-202, miR-539 and miR-620) with brooding were a function of childhood adversity, and both interaction findings were significantly present both in the never-depressed and in the ever-depressed group. Moreover, the association of rs3125 with brooding could be replicated across the separate subsamples, and remained significant even when controlling for lifetime depression and the Brief Symptom Inventory depression score. These findings indicate the crucial importance of involving stress factors when considering endophenotypes and suggest that brooding is a more promising endophenotype than a broader measure of rumination. Transdiagnostic relevance of the brooding endophenotype and the potential of targeting epigenetic regulatory polymorphisms of HTR2A in primary and secondary prevention of depression and possibly of other disorders are also discussed.