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Background: whether screening for skin cancer affects melanoma-specific mortality in a population-based setting remains unclear. Methods: in this population-based cohort study, we characterized and evaluated a skin cancer prevention program following a targeted screening approach conducted in 1989–1994 in the Austrian province Vorarlberg, with follow-up until 2019. The general population and attendees of a health examination program served for comparison. Results: in the screening program including full follow-up until 2019, 207 invasive and 187 in situ melanomas were identified in 8997 individuals. Incidences of invasive and in situ melanomas were elevated compared to the general population (IRR 2.92, 95%-CI 2.49–3.41, and IRR 4.13, 95%-CI 3.53–4.83, respectively) and the health examination program (HR 3.02, 95%-CI 2.59–3.52, and HR 3.90, 95%-CI 3.30–4.61, respectively). Breslow thickness and Clark’s level at time of invasive diagnosis were significantly lower in 1989–2019, but the tumor characteristics of the melanomas diagnosed during 1989–1994 did not differ from the comparison groups. Moreover, melanoma mortality was significantly elevated in the screening program (IRR 1.66, 95%-CI 1.00–2.75 vs. the general population, HR 2.12, 95%-CI 1.25–3.61 vs. the health examination cohort). Melanoma mortality in Vorarlberg declined until 2004, though statistically non-significantly. Conclusions: given the uncertain effectiveness and high public expenditures of population-wide mass screening programs, primary prevention and targeted risk-based skin cancer screening might be promising alternatives. Full article