BACKGROUND: Thoracic radiation results in radiation-associated heart disease (RAHD), often requiring cardiothoracic surgery (CTS). We sought to measure long-term survival in RAHD patients undergoing CTS, to compare them with a matched control population undergoing similar surgical procedures, and to identify potential predictors of long-term survival. METHODS AND RESULTS: In this retrospective observational cohort study of patients undergoing CTS, matched on the basis of age, sex, and type/time of CTS, 173 RAHD patients (75% women; age, 63±14 years) and 305 comparison patients (74% women; age, 63±4 years) were included. The vast majority of RAHD patients had prior breast cancer (53%) and Hodgkin lymphoma (27%), and the mean time from radiation was 18±12 years. Clinical and surgical parameters were recorded. The preoperative EuroSCORE and all-cause mortality were recorded. The mean EuroSCOREs were similar in the RAHD and comparison groups (7.8±3 versus 7.4±3, respectively; P=0.1). Proximal coronary artery disease was higher in patients with RAHD versus the comparison patients (45% versus 38%; P=0.09), whereas redo CTS was lower in the RACD versus the comparison group (20% versus 29%; P=0.02). About two thirds of patients in either group had combination surgical procedures. During a mean follow-up of 7.6±3 years, a significantly higher proportion of patients died in the RAHD group than in the comparison group (55% versus 28%; P<0.001). On multivariable Cox proportional hazard analysis, RAHD (2.47; 95% confidence interval, 1.82-3.36), increasing EuroSCORE (1.22; 95% confidence interval, 1.16-1.29), and lack of β-blockers (0.66; 95% confidence interval, 0.47-0.93) were associated with increased mortality (all P<0.01). CONCLUSIONS: In patients undergoing CTS, RAHD portends increased long-term mortality. Alternative treatment strategies may be required in RAHD to improve long-term survival.