The prognosis of melanoma patients who are diagnosed with multiple primary lesions remains controversial. We used a large population-based cohort to re-examine this issue, applying a delayed entry methodology to avoid survival bias. Of 32,238 eligible patients diagnosed between 1995 and 2008, 29,908 (93%) had a single invasive melanoma, 2,075 (6%) had two, and 255 (1%) had three. Allowing for differences in entry time, 10-year cause-specific survival for these three groups was 89% (95% confidence interval [CI] = 88–90%), 83% (95% CI = 80–86%), and 67% (95% CI = 54–81%), respectively. After adjustment for key prognostic factors, the hazard ratio of death within 10 years from melanoma was two times higher for those with two melanomas (hazard ratio = 2.01, 95% CI = 1.57–2.59; P < 0.001) and nearly three times higher when three melanomas were diagnosed (hazard ratio = 2.91, 95% CI = 1.64–5.18; P < 0.001) compared with people with a single melanoma. Melanoma-specific mortality remained elevated after adjusting for maximum thickness or ulceration of any melanoma regardless of the index tumor. After appropriately accounting for the interval between diagnosis of the first and subsequent melanomas, patients with multiple invasive melanomas have significantly poorer survival than patients with a single invasive melanoma.