OBJECTIVE: Ongoing debate focuses on whether patients admitted to the hospital on weekends have higher mortality than those admitted on weekdays. Whether this apparent "weekend effect" reflects differing patient risk, care quality differences, or inadequate adjustment for risk during analysis remains unclear. This study aimed to examine the existence of a "weekend effect" for risk-adjusted in-hospital mortality after cardiac surgery. DESIGN: Retrospective analysis of prospectively collected cardiac registry data. SETTING: Ten UK specialist cardiac centers. PARTICIPANTS: A total of 110,728 cases, undertaken by 127 consultant surgeons and 190 consultant anesthetists between April 2002 and March 2012. INTERVENTIONS: Major risk-stratified cardiac surgical operations. MEASUREMENTS AND MAIN RESULTS: Crude in-hospital mortality rate was 3.1%. Multilevel multivariable models were employed to estimate the effect of operative day on in-hospital mortality, adjusting for center, surgeon, anesthetist, patient risk, and procedure priority. Weekend elective cases had significantly lower mortality risk compared to Monday elective cases (odds ratio [OR] 0.64, 95% confidence interval [CI] 0.42, 0.96) following risk adjustment by the logistic European System for Cardiac Operative Risk Evaluation (EuroSCORE) and procedure priority; differences between weekend and Monday for urgent and emergency/salvage cases were not significant (OR 1.12, 95% CI 0.73, 1.72, and 1.07, 95% CI 0.79, 1.45 respectively). Considering only the logistic EuroSCORE but not procedure priority yielded 29% higher odds of death for weekend cases compared to Monday operations (OR 1.29, 95% CI 1.08, 1.54). CONCLUSIONS: This study suggests that undergoing cardiac surgery during the weekend does not affect negatively patient survival, and highlights the importance of comprehensive risk adjustment to avoid detecting spurious "weekend effects."