IMPORTANCE Little is known about survival after a diagnosis of a second or higher-order (multiple) primary melanoma, and no study has explored survival in a population-based sample that included patients with single primary melanomas (SPMs) and multiple primary melanomas (MPMs) of any stage. Because people with a first primary melanoma are known to have an increased risk of being diagnosed with another, evidence for prognosis is needed. OBJECTIVE To determine whether survival after diagnosis was better in patients with MPMs than with SPMs, as suggested in a recent study. DESIGN Survival analysis with median follow-up of 7.6 (range, 0.4-10.6) years. SETTING The Genes, Environment, and Melanoma Study enrolled incident cases of melanoma from population-based cancer registries in Australia, Canada, Italy, and the United States. Multiple primary melanomas were ascertained during a longer period than SPM. PARTICIPANTS Two thousand three hundred seventy-two patients with SPM and 1206 with MPM. EXPOSURE Diagnosis with melanoma. MAIN OUTCOMES AND MEASURES Melanoma-specific fatality hazard ratios (HR) and 95% confidence intervals associated with clinical and pathological characteristics of SPM, MPM, and both in Cox proportional hazards regression models. RESULTS Melanoma thickness was the main determinant of fatality (HR for >4 mm, 7.68 [95%CI, 4.46-13.23]); other independent predictors were ulceration, mitoses, and scalp location. After adjustment for these other predictors, we found little difference in fatality between MPM and SPM (HR for MPM relative to SPM, 1.24 [95%CI, 0.91-1.69; P = .18]). Thicker SPM, however, had higher fatality (HR for >4 mm, 13.56 [95%CI, 6.47-28.40]) than thicker MPM (2.93 [1.17-7.30]). CONCLUSIONS AND RELEVANCE Although overall fatalities due to SPM and MPM were similar, relative fatality for thicker SPM was greater than that for thicker MPM. This findingmay offer support for a difference in outcome between patients with SPM and MPM related to factors other than closer surveillance and earlier diagnosis. The better outcomes are worth further exploration.