Abstract Aims Anomalous origin of a coronary artery from the opposite sinus (ACAOS) has been associated with adverse cardiac events in the young. It remains unknown whether this holds true for middle-aged patients with uncorrected ACAOS as well. We assessed the outcome in middle-aged patients with newly diagnosed ACAOS by coronary computed tomography angiography (CCTA) compared with a matched cohort. Methods and results We retrospectively identified 68 consecutive patients with ACAOS documented by CCTA. ACAOS with a course of the anomalous vessel between the aorta and pulmonary artery were classified as interarterial course (IAC). Each patient with ACAOS was matched to two controls without ACAOS. Major adverse cardiac events (i.e. myocardial infarction, revascularization and cardiac death) were recorded for all patients and controls. Two (3%) patients were lost to follow-up. Thus, 66 patients with ACAOS were included in the final analysis and matched with 132 controls. Mean age of patients was 56 ± 11 years, 73% were male and the mean follow-up was 49 months. Forty (65%) patients were classified as having ACAOS with IAC. The annual event rate of ACAOS vs. controls was 4.9 and 4.8%, the hazard ratio (HR) 0.94 (0.39–2.28, P = 0.89). The annual event rate of ACAOS with IAC compared with their matched controls was 5.2 and 4.3%, and the HR 1.01 (95% CI 0.39–2.58, P = 0.99). Conclusions In middle-aged individuals with newly diagnosed ACAOS mid-term outcome is not statistically different to a matched control cohort without coronary artery anomalies, regardless of whether ACAOS with or without IAC variants are present.