Background: Worldwide, female melanoma patients have superior survival compared with males, which is usually ascribed to earlier detection among women and/or a more favorable site distribution. We studied gender difference in melanoma survival in a large population-based setting after adjusting for tumor-related variables and offer clues for further research. Patients and methods: A total of 10 538 patients diagnosed with melanoma from 1993 to 2004 in The Netherlands were included. Multivariate analyses were carried out to estimate adjusted relative excess risk (RER) of dying for men compared with women, adjusted for the patient and tumor characteristics. Results: Univariate relative survival analyses showed a RER of dying of 2.70 [95% confidence interval (CI) 2.38-3.06] for men compared with women. After adjusting for time period of diagnosis, region, age, Breslow thickness, histologic subtype, body site, nodal and metastatic status, a significant excess mortality risk was still present for males (RER 1.87, 95% CI 1.65-2.10). Among patients with advanced disease and in those < 45 or >= 60, the adjusted risk estimates were similar. Conclusions: The superior survival of women compared with men persisted after adjusting for multiple confounding variables indicating that factors other than stage at diagnosis and body site reduce mortality risk in female melanoma patients.