Purpose <p>To conduct a comprehensive analysis of the epidemiology, prognosis, and treatment of the head and neck mucoepidermoid carcinoma (HNMEC).</p> Methods <p>Patients diagnosed with HNMEC from 2004 to 2020 were retrieved from the Surveillance, Epidemiology, and End Results database. The demographic, clinicopathological and treatment-related characteristics of the cohort were described. Associations between categorical variables were examined by Pearson’s χ² test. The overall survival (OS) and disease-specific survival (DSS) were compared among groups using the log-rank test. Multivariate Cox analysis was used to adjust for confounding effects.</p> Results <p>A total of 6228 patients were included. The 5-year OS and DSS rates were 81.1% and 89.4%, respectively. Major salivary gland MEC accounted for the largest proportion, followed by oral cavity MEC. Oral cavity MEC exhibited the most favorable survival outcome, which may be due to the higher proportion of early-stage and low-grade disease. Patients with a history of cancer before or after diagnosis of HNMEC had worse OS, but not DSS. The patterns of local treatment for HNMEC remained unchanged from 2004 to 2020. Radiotherapy (alone or combined with surgery) was associated with a worse DSS, even after adjustment. Compared to patients diagnosed between 2004 and 2009, patients diagnosed between 2010 and 2015 had statistically significant improvements in both 5-year OS (3.7%) and 5-year DSS (3.4%).</p> Conclusion <p>A simplified 2-tierd grading system was appropriate for HNMEC, with Grade 1/2 being low-grade, and Grade 3/4 being high-grade. Tumor stage and grade are significant prognostic factors for HNMEC. Early-stage and low-grade HNMEC could be regarded as low-risk malignancy with favorable prognosis, which could usually be effectively treated with surgery alone.</p>