Women with myocardial infarction (MI) have shown a 28-day survival disadvantage compared with men. However, results were less consistent when considering long-term mortality in 28-day survivors. The aim was to estimate the trends for sex-related differences in the three endpoints considered for this study: (1) 28-day mortality or severe ventricular dysfunction (acute pulmonary oedema or cardiogenic shock) during the hospital stay, (2) 28-day mortality and (3) two-year cardiovascular mortality or non-fatal MI in 28-day survivors after a first MI. A cohort of 3,982 consecutive patients with first Q-wave MI admitted to a university tertiary reference hospital between 1978 and 2007 was followed for 2 years. Short-term prognosis improved in women over the studied period; similar rates were observed in both sexes in the 2000s. After adjusting for age, co-morbidities and anterior location of MI, female sex had an odds ratio=1.71 (95% confidence interval [CI] 1.34-2.17) of short-term severe MI or death over the studied period. Overall, sex differences in long-term prognosis remained similar over the studied period (hazard ratio=1.40; 95% CI 1.02-1.91). In conclusion, short-term prognosis improved over the past 30 years for first Q-wave MI patients, becoming similar for both men and women in the most recent decade. Long-term prognosis did not improve in either men or women, indicating that secondary prevention should be reinforced to achieve consistent reductions in the number of cardiovascular events.