This study investigated the association between OCS and the long-term prognosis of ACS in tandem with depression comorbidity and treatment. Methods A cross-sectional baseline study and a nested 24-week double-blind escitalopram-placebo controlled trial were carried out between May 2007 and March 2013, and then a 5–12-year follow-up for major adverse cardiac events (MACE) was conducted. A total of 1,152 patients with ACS were stratified by baseline depression comorbidity and treatment allocation into four groups: no depression (706 patients), depression and taking escitalopram (149 patients), depression and taking a placebo (151 patients), and depression and receiving medical care as usual (CAU; 146 patients). OCS were evaluated using the Symptom Checklist-90-Revised Obsessive-Compulsive symptom domain. During the follow-up, Kaplan-Meier event rates for MACE outcomes were calculated, and hazard ratios were estimated using Cox regression models after adjusting for a range of covariates. Results A higher OCS score at baseline was associated with a worse ACS prognosis after adjusting for relevant covariates and across MACE outcomes. This association varied according to the depression comorbidity. The association was significant in patients without depression and depressive patients receiving placebos and CAU, but not in depressive patients on escitalopram. Conclusion Evaluating OCS and depression is recommended during the early phase of ACS. Treatment for OCS may improve the longterm cardiac outcomes of patients with ACS.