Background: From July 1, 2003 to June 30, 2004, a population-based skin cancer screening project was conducted in Schleswig-Holstein, Germany. In total, 360,288 individuals aged ≥20 years were screened by means of a whole-body examination. In this report, the authors compare trends in melanoma mortality in Schleswig-Holstein with those in all adjacent regions, none of which had population-based skin cancer screening. Methods: Trends in melanoma mortality rates for Schleswig-Holstein and the adjacent regions (Denmark and the German federal states of Mecklenburg-Vorpommern, Hamburg, and Lower Saxony) and in Germany excluding Schleswig-Holstein were compared. Log-linear regression was used to assess mortality trends. Results: In Schleswig-Holstein during the pre skin cancer screening period (1998-1999), the age-standardized melanoma mortality rate (World standard population) was 1.9 per 100,000 for men and 1.4 per 100,000 for women. Melanoma mortality declined by 47% to 1.0 per 100,000 men and by 49% to 0.7 per 100,000 women by 2008/2009. The annual percentage change in the most recent 10-year period (2000-2009) was -7.5% (95% confidence interval, -14.0, -0.5) for men and -7.1% (95% confidence interval, -10.5, -2.9) for women. In each of the 4 adjacent regions and in the rest of Germany, mortality rates were stable, and the decline in Schleswig-Holstein was significantly different from the changes observed in all of the other areas studied. Conclusions: The current data represent strong evidence, but not absolute proof, that the skin cancer screening program produced a reduction in melanoma mortality in Schleswig-Holstein. Cancer 2012.