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Background: Although psychological factors play a significant role in the onset and prognosis of acute coronary syndrome (ACS), psychological interventions (PIs) are rarely included in cardiac rehabilitation (CR) programs due to inconclusive evidence regarding specific intervention components and effect sizes. This study aimed to assess the efficacy of a PI based on cognitive-behavioral treatment (CBT) and positive psychology therapy (PPT) in improving psychological and clinical outcomes in patients with ACS. Methods: This PsicoCare trial was an open-label randomized controlled trial that compared a combined CBT and PPT-based PI (the PsicoCare program) with a standard CR program (control group). We recruited 87 ACS patients, and psychological outcomes, functional capacity, biochemical and anthropometric measures, and clinical outcomes were assessed at baseline, 2 months, and 9 months after the ACS event. Results: The PsicoCare group showed significant improvements in depression, anger traits, anger-in, and anger control-out compared to the control group. Additionally, the PsicoCare intervention was associated with the improved maintenance of cognitive function, social support, and spiritual coping styles, while the control group showed deterioration in these areas. Patients experiencing severe ACS showed significant improvement in personal strength and meaning as a result of the PsicoCare intervention. However, no significant effects were observed on anxiety, anger-out, emotion regulation skills, dispositional optimism, other personal strengths, or quality of life. Both groups demonstrated similar improvements in functional capacity and clinical outcomes. Conclusion: The study suggests that CBT and PPT-based PIs may offer additional benefits for ACS patients, particularly regarding their psychological health. Further larger trials are required to confirm these findings. Clinical trial registration: identifier, NCT05287061. [ABSTRACT FROM AUTHOR]