PURPOSE To retrospectively analyze a series of mucosal melanoma of the upper aerodigestive tract to determine the prognostic factors and contribute to understanding the role of radiotherapy in the therapeutic strategy. METHODS AND MATERIALS Seventy-four patients were analyzed. The most frequent locations were nasal and oral, in 31 patients (41.9%) and 12 patients (16.2%), respectively. Sixty-three patients (85.1%) were in Stage I, 5 (6.8%) in Stage II, and 6 (8.1%) in Stage III. Treatment consisted of surgery in 17 patients (23.0%), surgery and radiotherapy in 42 (56.8%), radiotherapy in 11 (14.9%), and chemo-immunotherapy in 4 (5.4%). Median follow-up was 20 months. RESULTS Local control at 3 years was 57% after surgery alone and 71% after surgery and radiotherapy. Overall and disease-free survival rates, respectively, were 41% and 31% at 3 years and 14% and 22% at 10 years. After univariate analysis, female gender, melanosis, tumor size </=3 cm, Stage I, postoperative radiotherapy, and complete remission were favorable prognostic factors. Stage I and melanosis were confirmed by multivariate analysis. CONCLUSIONS Local control was improved by postoperative radiotherapy, despite survival being as poor as in other published series. Stage I and melanosis at diagnosis were the most favorable prognostic factors.