The association between physical activity, diabetes mellitus (DM), and long-term acute coronary syndrome (ACS) prognosis was evaluated. The GREECS study included 2,172 consecutive ACS patients from six Greek hospitals (2003–2004). In 2013–2014, a 10-year follow up was performed with 1,918 patients. Physical activity was categorized in never, rarely (monthly basis), 1–2 and ≥ 3 times/week. Multi-adjusted analysis revealed that 1–2 and ≥ 3 times/week vs. no physical activity had a protective effect on ACS incidence (OR = 0.63 95% CI 0.38, 1.05) and (OR = 0.63 95% CI 0.40, 0.99) respectively, only in patients without prior baseline CVD event. In a subgroup analysis, with DM as strata in these patients, engagement in physical activity (i.e., 1–2 times/week) had a significant protective effect among patients with diabetes (OR = 0.51, 95% CI 0.27, 0.96,
p= .037). These findings revealed the beneficial role of exercise in secondary ACS prevention, even in DM patients. Public health-oriented policies should incorporate regular physical activity as a key protective factor in disease prognosis.