Objective: To explore the psychosocial determinants and interhospital variability on a major acute cardiovascular event (MACE), during follow-up of a multicenter cohort of patients hospitalised with heart disease, participating in a nurse-led secondary prevention programme. Methods: Outcome data were retrospectively analysed from 602 cardiac inpatients randomised to postdischarge standard care (n=296), or home-based intervention (n=306), with prolonged follow-up of individualised multidisciplinary support. Baseline psychosocial profiling comprised depressive status, health-related quality of life (HRQoL), social isolation and mild cognitive impairment (MCI). Multivariate analyses examined the independent correlates of a composite 2-year MACE rate of all-cause mortality and unplanned cardiovascular-related hospitalisation, according to gender. Results: Participants were aged 70±10 years, 431 (72%) were men and 377 (63%) had coronary artery disease. During 2-year follow-up, 165 (27%) participants (114 men, 51 women; p=0.431) experienced a MACE. Independent correlates of a MACE in men were depressive status (OR 1.95, 95% CI 1.06 to 3.58; p=0.032), low physical HRQoL (OR 0.98, 95% CI 0.96 to 1.00; p=0.027) and increasing comorbidity (OR 1.14, 95% CI 1.04 to 1.25; p=0.004). In women, age (OR 1.06, 95% CI 1.02 to 1.12; p=0.008), MCI (OR 2.38, 95% CI 1.09 to 5.18; p=0.029) and hospital site predicted a MACE (OR 2.32, 95% CI 1.09 to 4.93; p=0.029). Conclusions: Psychological determinants, cognitive impairment and responses to secondary prevention are different for men and women with heart disease and appear to modulate cardiovascular-specific outcomes. Early detection of psychosocial factors through routine screening and gender-specific secondary prevention is encouraged.