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BACKGROUND Melanoma in situ (MIS) is among the most frequently diagnosed cancers in the United States. Emerging data suggest that MIS is associated with an increased risk of developing a second primary malignancy (SPM). OBJECTIVES To determine trends in MIS-associated SPMs and identify MIS-specific features that increase SPM risk. METHODS In this retrospective population-based study, we identified 90,075 patients who were diagnosed with MIS between 1973 and 2015 from the Surveillance, Epidemiology, and End Results database. The risk of developing an SPM among these individuals was compared to individuals without a diagnosis of MIS. The risk of developing an SPM among patients with a diagnosis of MIS was also increased over time. RESULTS Patients with a diagnosis of MIS had an increased relative risk (RR) of developing an SPM as compared to the general population with an identical age, sex, race, and follow-up period. The RR of a metachronous malignancy in MIS patients also increased over time, as follows: 1.16 (95 % CI: 1.07-1.26), 1.19 (95 % CI: 1.14-1.23), 1.30 (95 % CI: 1.27-1.33), and 1.52 (95 % CI: 1.49-1.56) in 1973-1982, 1983-1992, 1993-2002, and 2003-2015, respectively (P < 0.05). In addition, there was a direct correlation between the number of MIS lesions and SPM risk; ≥1, ≥2, and ≥3 tumors portended a 1.5-2, 2-3, and 4-5-fold increased risk of developing an SPM, respectively. CONCLUSIONS MIS is associated with an increased risk of developing an SPM and therefore individuals with a history of MIS may benefit from close medical surveillance.