Background: The incidence of skin cancer is increasing worldwide. For decades, opportunistic melanoma screening has been carried out to respond to this burden. However, despite potential positive effects such as reduced morbidity and mortality, there is still a lack of evidence for feasibility and effectiveness of organized skin cancer screening. Objective: The main aim of the project was to evaluate the feasibility of systematic skin cancer screening. Methods: In 2003, the Association of Dermatological Prevention was contracted to implement the population-based SCREEN project (Skin Cancer Research to Provide Evidence for Effectiveness of Screening in Northern Germany) in the German state of Schleswig-Holstein. A two-step program addressing malignant melanoma and nonmelanocytic skin cancer was implemented. Citizens (aged ≥20 years) with statutory health insurance were eligible for a standardized whole-body examination during the 12-month study period. Cancer registry and mortality data were used to assess first effects. Results: Of 1.88 million eligible citizens, 360,288 participated in SCREEN. The overall population-based participation rate was 19%. A total of 3103 malignant skin tumors were found. On the population level, invasive melanoma incidence increased by 34% during SCREEN. Five years after SCREEN a substantial decrease in melanoma mortality was seen (men: observed 0.79/100,000 and expected 2.00/100,000; women: observed 0.66/100,000 and expected 1.30/100,000). Limitations: Because of political reasons (resistance as well as lack of support from major German health care stakeholders), it was not possible to conduct a randomized controlled trial. Conclusions: The project showed that large-scale systematic skin cancer screening is feasible and has the potential to reduce skin cancer burden, including mortality. Based on the results of SCREEN, a national statutory skin cancer early detection program was implemented in Germany in 2008.