Abstract Colon medullary adenocarcinoma (MAC) is a rare histologic subtype. Clinical presentation and cancer outcomes of MAC, compared to colon adenocarcinoma (AC), remain incompletely described. Annual age-adjusted incidence rates were computed using Surveillance, Epidemiology, and End Results (2002–2017). A cohort analysis using the National Cancer Database (2010–2016) compared patient characteristics in an unmatched dataset and prognostic characteristics in a 1:1 matched subset. Reported annual age-adjusted incidence of MAC has significantly increased, with an average annual percent change (APC) increase of 23.8% (95% CI: 19.2–28.6); concurrent AC incidence declined (APC: − 2.8, 95% CI: − 3.1 to − 2.8). Analyses of 1018 MAC and 210,784 AC unmatched patients showed that MAC patients were more often older, female, and white, with higher disease stage, poorly-differentiated tumors, right-sided laterality, and lymphovascular invasion (all p