Background: Although ASCO revised Guidelines (2013) recommends referring to psychological professionals if cancer patients show concerns or anxiety about fertility, there is no evidence regarding the efficacy of psychotherapy. The aim of this study is to examine whether the Psycho-Education And Couple Enrichment (O!PEACE) therapy can reduce psychiatric symptoms and improve stress coping and marital relationship in breast cancer patients. Methods: Trial design: multicenter randomized controlled trial, pre-post design. Subjects were women aged 20–39 years with breast cancer before cancer treatment and their husbands. Couples were randomly assigned to receive O!PEACE therapy (n = 37) or not (usual care: n = 37). Assessments of PTSD symptoms, depression and anxiety were made as the primary end points at baseline and at the end of therapy before cancer treatment. Stress coping strategies, resilience, marital relationships, and marital communication were examined as secondary end points. Results: Four participants in O!PEACE therapy and one participant in the usual care withdrew from the trial. Intention-to-treat analyses were conducted using analysis of covariance after multiple imputation by R and SPSS. Series of ANCOVAs were integrated according to Rubin’s rule. A significant decrease was observed in the primary outcome of PTSD symptoms, from baseline to post-intervention, in women who participated in O!PEACE therapy (p = .011, η_p² = .089). According to post-hoc analyses, for patients with a higher baseline IES-R-J score, O!PEACE therapy resulted in a significantly higher reduction in follow-up assessment IES-R-J score when compared with usual care (U = 172.80, p = .027, r = .258): 59.3% of the women in O!PEACE therapy showed a 5-point or greater reduction, whereas in usual care, 30.0% showed a 5-point or greater reduction. For husbands, the O!PEACE therapy also showed a significant improvement of giving up and blaming others as the stress coping strategy and escape-avoidance coping strategy in their marital communication. For breast cancer patients, the O!PEACE therapy significantly improved support from husbands and the patients’ knowledge level of oncofertility compared with those receiving usual care. Conclusions: Only two counseling sessions of O!PEACE therapy can reduce patients’ distress, improve their husbands’ coping style, and may build a better cooperative relationship for couples in terms of fertility preservation and cancer treatment. Clinical trial information: UMIN000017754.