The occurrence of second primary tumors (SPTs) following adjuvant therapy for resected stages II and IIIa non-small cell lung cancer (NSCLC) was investigated. Data regarding SPTs were prospectively collected in all patients accrued to Eastern Cooperative Group Oncology E3590 (a phase III trial of adjuvant therapy in patients with completely resected stages II and IIIa NSCLC). Four hundred eighty-eight patients were accrued to the study, 242 to the RT arm and 246 to the CRT arm. Median follow-up was 73 months. Thirty patients (6.1%) developed 33 SPTs, 20 in the RT arm and ten in the CRT arm. Ten SPTs occurred within the upper aerodigestive tract, six in the RT arm and four in the CRT arm. Twenty-three SPTs occurred in other organs, 17 in the RT arm and six in the CRT arm. Median time to detection of a SPT for those patients randomized to RT and CRT was 43 and 36 months, respectively. The incidence of SPTs was 1.8% per patient-year of follow-up. Excluding skin tumors, the relative risk of death following diagnosis of a SPT for patients randomized to the CRT arm as compared with those randomized to RT alone was 2.26 (95% confidence interval, 0.78-5.58, P=0.12). Patients are at risk for developing a SPT following resection of stages II and IIIa NSCLC. The majority of SPTs occur outside the aerodigestive tract. Following development of a non-skin SPT, the survival difference between patients who had received adjuvant CRT and those treated with adjuvant RT alone was not significant.