Early-onset colorectal cancer (EOCRC) has an alarmingly increasing trend and arouses increasing attention. Causes of death in EOCRC population remain unclear.Data of EOCRC patients (1975-2018) were extracted from the Surveillance, Epidemiology, and End Results database. Distribution of death was calculated, and death risk of each cause was compared with the general population by calculating standard mortality ratios (SMRs) at different follow-up time. Univariate and multivariate Cox regression models were utilized to identify independent prognostic factors for overall survival (OS).The study included 36,013 patients, among whom 9,998 (27.7%) patients died of colorectal cancer (CRC) and 6,305 (17.5%) patients died of non-CRC causes. CRC death accounted for a high proportion of 74.8%-90.7% death cases within 10 years, while non-CRC death (especially cardiocerebrovascular disease death) was the major cause of death after 10 years. Non-cancer death had the highest SMR in EOCRC population within the first year after cancer diagnosis. Kidney disease [SMR = 2.10; 95% confidence interval (CI), 1.65-2.64] and infection (SMR = 1.92; 95% CI, 1.48-2.46) were two high-risk causes of death. Age at diagnosis, race, sex, year of diagnosis, grade, SEER stage, and surgery were independent prognostic factors for OS.Most of EOCRC patients died of CRC within 10-year follow-up, while most of patients died of non-CRC causes after 10 years. Within the first year after cancer diagnosis, patients had high non-CRC death risk compared to the general population. Our findings help to guide risk monitoring and management for US EOCRC patients.Copyright © 2023 Chen, He, Lu, Tang, Luo, Chen, Wu, Liang and Xu.