<b><i>Introduction:</i></b> Obsessive-compulsive disorder (OCD) is associated with high chronicity and treatment resistance, indicating the need for early therapy response markers enabling fast and personalized treatment adaptations. Although epigenetic mechanisms such as DNA methylation of the oxytocin receptor <i>(OXTR)</i> gene have previously been linked to OCD pathogenesis, epigenetic markers as predictors of treatment success have not yet been investigated in OCD. <b><i>Objective:</i></b> For the first time, this therapyepigenetic study aimed to investigate the role of <i>OXTR</i> methylation as a treatment response marker in OCD. <b><i>Methods:</i></b> In total, 113 inpatients with OCD (57 females) were compared to 113 age- and sex-matched healthy controls. Patients were investigated over a 10-week course of standardized, OCD-specific cognitive-behavioral psychotherapy. Clinical response was measured using the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) at baseline, before in vivo exposure, and after therapy. <i>OXTR</i> exon III methylation was analyzed via direct sequencing of sodium bisulfite-treated DNA extracted from blood cells. <b><i>Results:</i></b> Relative <i>OXTR</i> hypermethylation was observed in OCD patients compared to healthy controls. In OCD, higher baseline <i>OXTR</i> methylation was found to predict impaired treatment response at both categorical (responders vs. nonresponders) and dimensional (relative Y-BOCS reduction) levels, whereas lower baseline methylation was related to treatment response and greater symptom improvements. Analysis of Y-BOCS subdimensions revealed that the association between <i>OXTR</i> hypermethylation with impaired treatment response applied especially to symptoms related to obsessions, but not compulsions. <b><i>Conclusions:</i></b> <i>OXTR</i> hypermethylation may constitute a predictive marker of impaired treatment response in OCD and thus carries great potential for future personalized treatment efforts in OCD.