There is limited evidence whether women benefit to the same degree as men from treatment of myocardial infarction with percutaneous coronary intervention (PCI) when compared to fibrinolysis. This study compares health-related quality of life (HRQoL) outcomes for men and women randomized to primary PCI and fibrinolysis. A questionnaire-based study in 1351 patients with ST-elevation myocardial infarction (STEMI), assessed at 1 and 12 months after the infarction. HRQoL was measured with the Medical Outcomes Study Short Form (SF-36), the Hospital Anxiety and Depression Scale (HADS), Rose's angina and dyspnoea questionnaire and global QoL questions. Women had a worse score than men on all endpoints at 1 month and at several endpoints at 12 months. In analyses of gender differences in benefits of PCI 1 month after the STEMI, significant gender differences were found in the SF-36 mental component summary scale, with men having better scores after primary PCI and women having better scores after fibrinolysis (P=0.03). At 12 months, similar gender differences in treatment benefit were found in the SF-36 scales for general health (P=0.01), mental health (P<0.01), and the mental component summary scale (P=0.01), as well as in the scales for anxiety (P=0.04), depression (P=0.02), and global quality of life (P<0.01); men had better scores after primary-PCI and women had better scores after fibrinolysis. Compared to fibrinolysis treatment in patients with ST-elevation myocardial infarction, women do not seem to benefit from primary PCI to the same degree as men. Since previous studies have found no gender differences in clinical outcomes, this result may be specific to HRQoL.