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Melanoma may present metastatically without an identifiable primary lesion. To further characterize the epidemiology of melanoma of unknown primary (MUP), we report our experience with a cohort of MUP patients. We retrospectively reviewed patients seen at the Massachusetts General Hospital (MGH) and the Dana-Farber Cancer Institute (DFCI) between 1986 and 1996 with follow-up to 2002. Data were analysed using log-rank and proportional hazards analyses, with death from any cause as the main outcome measure. Of the 2485 melanoma patients seen, 65 (2.6%) had MUP; 41 patients were male [63.1%; 95% confidence interval (CI), 50.2%, 74.7%]. The median age at diagnosis was 54.1 years (interquartile range, 39.4-67.1 years). Thirty patients had lymph node metastases, 12 cutaneous or subcutaneous metastases and 23 visceral metastases. Of the 62 patients (95.4%) with at least some follow-up, there were 42 deaths from any cause. Patients with lymph node metastases survived significantly longer than patients with other metastases [5-year survival 38.7% (95% CI, 18.1%, 59.1%) vs. 13.9% (95% CI, 4.4%, 28.6%); P<0.01]. After adjusting for stage and age at diagnosis, there was some evidence that men survived longer than women [hazard ratio (HR)=0.55; 95% CI, 0.28, 1.09]. Survival did not differ amongst patients with different types of non-lymph node metastases. The 5-year survival rates in this cohort did not differ from those of historical controls with known primaries. The demographic and survival characteristics of this MUP cohort mirrored those found in previous studies. More studies of MUP patients, as well as a standardized definition of MUP, may shed light on the pathogenesis and prognosis of MUP.