Purpose: Findings from Radiation Therapy Oncology Group (RTOG) 0617 suggested that collateral radiation to the heart may contribute to early death in patients receiving chemoradiation therapy for non-small cell lung cancer (NSCLC); however, reports of cardiac toxicity after thoracic radiation therapy (RT) remain limited. Because pericardial disease is the most common cardiac complication of thoracic RT, we investigated the incidence of and risk factors for pericardial effusion (PCE) in patients enrolled in a phase 2 prospective randomized study of intensity modulated RT versus proton therapy for locally advanced NSCLC. Methods and Materials: From July 2009 through April 2014, 201 patients were prospectively treated with proton beam therapy or intensity modulated RT to 60 to 74 Gy with concurrent chemotherapy. The primary endpoint (grade >= 2 PCE) was diagnosed on review of follow-up images. Clinical characteristics and cardiac dose-volume parameters associated with PCE were identified via Cox proportional hazards modeling and recursive partitioning analysis of null Martingale residuals. Reproducibility was evaluated in a separate retrospective cohort of 301 patients. Results: The cumulative incidence rates of PCE among patients in the trial were 31.4% at 1 year and 45.4% at 2 years, with a median time to PCE of 8.9 months. Several cardiac dose-volume parameters (eg, V20 [volume receiving >= 20 Gy] to V65 [volume receiving >= 65 Gy]) predicted PCE, but heart volume receiving >= 35 Gy (HV35) was the most strongly associated, with a cutoff volume of 10%. On multivariate analysis, HV35 > 10% independently predicted PCE (hazard ratio [HR], 2.14; P=. 002), a finding that maintained reproducibility in the retrospective validation cohort. Other factors associated with PCE included receipt of adjuvant chemotherapy (HR, 2.82; P<. 001) and prior cardiac disease (HR, 1.68; P=. 020). Conclusions: PCE was common after RT for NSCLC, occurring in nearly half of patients even after moderate radiation doses to the heart. Adjuvant chemotherapy may increase the risk of PCE, and HV35 > 10% may identify patients at risk of development of this cardiac toxicity. (C) 2017 Elsevier Inc. All rights reserved.