Background: Smoking has been associated with higher morbidity and mortality following myocardial infarction (MI), but reports of the impact on morbidity and mortality for females and elderly patients experiencing MI complicated with left ventricular dysfunction or overt heart failure are limited. Materials and Methods: In an individual patient data meta-analysis of high-risk MI patients, the association of smoking with hospitalizations and death were investigated. Weighted Cox proportional hazard modeling were used to study the risks of smoking on adjudicated endpoints among different sex and age categories. Results: Twenty-eight thousand seven hundred thirty-five patients from the CAPRICORN, EPHESUS, OPTIMAAL, and VALIANT trials were assessed. After weighting, smokers (N = 18,148) were unfrequently women (29.2%) and a minority were above ≥80 years (9.8%). Smoking was significantly more associated with all-cause hospitalizations in women (hazard ratio [HR] 1.24; 95% confidence interval [95% CI] 1.16-1.32) than in men (HR = 1.10; 95% CI 1.05-1.16) resulting in a significant interaction between smoking and sex (p = 0.005). Smoking was predictive of all-cause mortality homogenously across age categories (p for interaction = 0.25) and sex (p for interaction = 0.58). Conclusions: The influence of smoking on morbidity differed according to sex following high-risk MI. The deleterious impact of smoking on hospitalization appeared particularly potent in women, which should further reinforce preventive strategies in females.