Primary mediastinal seminoma (PMS) was an uncommon carcinoma, and the appropriate treatment remained controversial due to the low incidence. We aimed to investigate the demographics and tumor biological characteristics to determine the potential effective treatment and predict the prognosis.Patients diagnosed with PMS were selected between 1975 and 2016 from Surveillance, Epidemiology, and End Results (SEER) database. Kaplan-Meier analysis and Cox proportional hazard model were conducted to determine the prognostic factors, and nomograms were employed to visually predict the prognosis. Concordance index (C-index), calibration curve, and receiver operating characteristic (ROC) curve were conducted to validate the prediction model.A total of 476 patients were included with a median age of 31 years (range, 2-76 years), and a median size of the tumor was 11.6 cm (range, 0.2-24.0 cm). The 5- and 10-year overall survival (OS) rates were 70.4% and 68.4%, respectively. Age, the extent of the primary site, metastatic status, and surgery performance were independent prognostic factors. Not received surgery was considered a poor prognostic factor for OS (HR, 1.86; 95% CI, 1.13-3.03; P=0.013). The C-index was 0.733 (95% CI, 0.685-0.781) and 0.819 (95% CI, 0.737-0.901) for internal and external validation for predicting OS, respectively. The area under the ROC curve (AUC) was 0.743 (95% CI, 0.681-0.804) for predicting OS (sensitivity, 0.532; specificity, 0.887) in the training cohort.The nomogram could efficiently predict the survival of patients with PMS. Surgery was the potential effective treatment, and chemotherapy was strongly recommended for patients over 40 years.Copyright © 2021 Weijia Huang et al.