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Mediastinal radiation therapy (MRT) increases the risk for adverse outcomes after cardiac surgery and is not incorporated in the Society of Thoracic Surgeons (STS) risk algorithm. We aimed to quantify the surgical risk conferred by MRT in patients undergoing primary and reoperative valvular operations.A retrospective analysis of 261 consecutive patients with prior MRT who underwent valvular operations between January 2002 and May 2015. Short- and long-term outcomes were compared for STS predicted risk of mortality, surgery type, gender, year of surgery, and age-matched patients stratified by reoperative status.Mean age was 62.6 ± 12.1 years and 174 (67%) were women. The majority had received MRT for Hodgkin lymphoma (48.2%) and breast cancer (36%). Overall, 214 (82%) were primary and 47 (18%) were reoperative procedures. Reoperation carried a higher operative mortality than primary cases (17% vs 3.7%; P = .003). Compared with the 836 nonradiated matches, operative mortality and observed-to-expected STS mortality ratios were higher in primary (3.8% [1.4] vs 0.8% [0.32]; P = .004) and reoperative (17% [3.35] vs 2.3% [0.45]; P = .001) patients with prior MRT. Cox proportional hazard modeling revealed that in patients with previous MRT, primary (hazard ratio, 2.24; 95% confidence interval, 1.73–2.91) and reoperative status (hazard ratio, 3.19; 95% confidence interval, 1.95–5.21) adversely affected long-term survival compared with nonradiated matches.Surgery for radiation-induced valvular heart disease has a higher operative mortality than predicted by STS predicted risk of mortality. Reoperations are associated with increased morbidity and mortality compared with primary cases. Careful patient selection is paramount and expanded indications for transcatheter therapies should be considered, especially in reoperative patients.