To identify patients with melanoma at risk for a second primary lesion and to assess the prognostic relevance of multiple primary lesions, 7816 patients treated for malignant melanoma have been reviewed. Two to nine primary lesions were identified in 283 patients (3.6%): two lesions were identified in 82% of these 283 patients, three lesions in 11%, and four lesions in 3%. Sixty-four percent were metachronous. Among patients with melanoma, the 10-year actuarial risk of a second primary lesion was 5%; a third of that risk was expressed within 3 months of the initial diagnosis plus a subsequent risk of 0.38% per year. Risk factors for multiple primary lesions were family history of melanoma, thin primaries, male sex, Celtic complexion, and a history of another cancer. Patients with a family history of melanoma had a 14% risk of a second primary lesion during the first 10 years after diagnosis. By univariate and multivariate analyses, there was no survival disadvantage for patients with multiple primary lesions. After median follow-ups of 3.7 and 4.8 years, respectively, 51.7% and 50.5% of the groups with single and multiple primaries were disease free. Mortality rates were 31% and 25%, respectively. It is appropriate to base therapeutic decisions and prognostic evaluations on the specific risk factors of each individual lesion. Identification of patients at high risk for multiple primary lesions may permit early diagnosis and improved outcomes.