Abstract Until now, it remains unclear how to best use the histological subtype in clinical practice. This study aimed to compare differences in the efficacy of postoperative chemotherapy among different histological subtypes of colon adenocarcinomas. Using the Surveillance, Epidemiology, and End Results‐Medicare database, 51,200 patients with stage II or III primary colon carcinomas who underwent resection for curative intent between 1992 and 2008 were included. The survival benefit was evaluated using a Cox proportional hazards model, interaction analyses, and propensity score‐matched techniques. There was no significant difference in survival for low‐risk stage II mucinous adenocarcinoma (MA) or nonmucinous adenocarcinoma (NMA) between 5‐FU and oxaliplatin‐treated groups (P = 0.387 for MA, P = 0.629 for NMA). Patients with high‐risk stage II NMA who received the oxaliplatin chemotherapy regimen had significantly improved cancer‐specific survival (CSS) compared with the 5‐FU group (P = 0.004), while those with MA saw no improvement (P = 0.690). For stage III tumors, patients with NMA who received the oxaliplatin chemotherapy regimen had significantly improved CSS compared with the 5‐FU group (P
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