Background Little attention has been paid to the importance of sex in the long‐term prognosis of patients undergoing cardiac surgery. Methods and Results We conducted a retrospective cohort study of Ontario residents, aged ≥40 years, who underwent coronary artery bypass grafting (CABG) and/or aortic, mitral, or tricuspid valve surgery between October 1, 2008, and December 31, 2016. The primary outcome was all‐cause mortality. The mortality rate in each surgical group was calculated using the Kaplan‐Meier method. The risk of death was assessed using multivariable Cox proportional hazard models. Sex‐specific mortality risk factors were identified using multiplicative interaction terms. A total of 72 824 patients were included in the study (25% women). The median follow‐up period was 5 (interquartile range, 3–7) years. The long‐term age‐standardized mortality rate was lowest in patients who underwent isolated CABG and highest among those who underwent combined CABG /multiple valve surgery. Women had significantly higher age‐standardized mortality rate than men after CABG and combined CABG /mitral valve surgery. Men had lower rates of long‐term mortality than women after isolated mitral valve repair, whereas women had lower rates of long‐term mortality than men after isolated mitral valve replacement. We observed a statistically significant association between female sex and long‐term mortality after adjustment for key risk factors. Conclusions Female sex was associated with long‐term mortality after cardiac surgery. Perioperative optimization and long‐term follow‐up should be tailored to younger women with a history of myocardial infarction and percutaneous coronary intervention and older men with a history of chronic obstructive pulmonary disease and depression.