The most common form of therapy for non-small cell lung cancer (NSCLC) in early stage is surgery-based combination therapy, including radiotherapy and immunotherapy. However, postoperative radiotherapy (PORT) of cancer is correlated with increasing risk of second primary malignancy (SPM), especially young-onset cancer cases. We aimed to quantify the risks of SPM associated with PORT treatment for young‑onset NSCLC in early stage.We screened for SPM that developed over 5 years since the diagnosis of NSCLC. Using the data from the Surveillance, Epidemiology and End Results database, PORT-correlated risks were estimated with multivariate Logistic regression analysis. Moreover, Fine-Gray's competing risk regression analysis was used to calculate the cumulative incidence of SPMs.Among the 30308 young-onset NSCLC patients in early stage undergoing surgery, a total of 3728 patients have received PORT. Logistic regression analyses showed that PORT showed substantial correlation with elevated risks of second solid malignancies (RR = 1.31; 95% CI: 1.17-1.46), lung cancer (RR=1.23; 95% CI: 1.07-1.42), breast cancer (RR=1.74; 95% CI: 1.16-2.74) and colon and rectum cancers (RR=1.37; 95% CI: 1.07-2.06) as well as a negligible risk of second hematologic malignancies (RR = 1.15; 95% CI: 0.82-1.67). The cumulative incidence of SPMs revealed similar findings. Higher RR was obtained in NSCLC patients aged 60 to 69 years (RR = 1.33), in white race (RR = 1.36), diagnosed in 1975-2000 (RR = 1.23) and 2001-2015 (RR = 1.40), or diagnosed with lung adenocarcinoma (RR = 1.55).PORT for young-onset NSCLC in early stage was correlated with elevated risks of SPMs (lung cancer, breast cancer as well as colon and rectum cancers), supporting the need for long-term surveillance of these patients.Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.