IMPORTANCE: Several epidemiological studies show an alarming global increase in incidence of melanoma and nonmelanoma skin cancer. OBJECTIVES: To examine the cost-effectiveness of 2 population-based skin cancer screening methods and to assess their budget effect and the influence on skin cancer epidemiological findings. DESIGN, SETTING, AND PARTICIPANTS: A Markov model with a latent period of 20 years and a time horizon of 50 years was used to analyze the cost-effectiveness (societal perspective) and budget effect (public health care payer perspective) of 2 population-based skin cancer screening programs in Belgium compared with the absence of a screening program. A health economic analysis was based on a clinical trial performed in 2014 in Belgium. In the economic model, the total Belgian population 18 years or older was assumed to have been invited for the screening program. MAIN OUTCOMES AND MEASURES: The influence of the screening program on skin cancer epidemiological findings and the cost per quality-adjusted life-year (QALY) gained, as well as the budget effect, expressed as the net costs for the health care payer over 50 years. RESULTS: All participants (1668 total-body skin examination [TBSE] and 248 lesion-directed screening [LDS]) were screened by a team of 6 dermatologists from March 14 to 18, 2014, for TSBE and April 22 and 25 to 27, 2014, for LDS. Both screening strategies produced a gain in QALYs, resulting in incremental cost-effectiveness ratios of €33 072 (US $35 475) per QALY in men and €18 687 (US $20 044) per QALY in women for TBSE and €34 836 (US $37 365) per QALY in men and €19 470 (US $20 884) per QALY in women for LDS. With a 1-time screening, a 4.0% decrease in the incidence rates of stage III and IV melanoma was predicted at the population level relative to the comparator. The budget effect analysis demonstrated that during 20 years, a 1-time screening would incur a net cost for the health care payer of almost €36 million (US $38.6 million) for TBSE or just over €6 million (US $6.4 million) for LDS (€4.1 [US $4.40] or €0.7 [US $0.80], respectively, per adult). CONCLUSIONS AND RELEVANCE: These results can be interpreted as cost-effective at a willingness-to-pay threshold in Belgium of €35 000 (US $37 541) per QALY gained. Based on these findings, a 1-time TBSE in the general adult population 18 years or older is the most cost-effective strategy and is predicted to result in a reduction of skin cancer mortality over 20 years and 50 years. The cost-effectiveness for skin cancer screening is higher in women than in men.