Background: Many melanomas and keratinocyte cancers (KC) are preventable by reducing sun exposure and improving sun protection behaviors. Recent evidence indicates a melanoma prevention program involving personalized genomic risk information provision can reduce self-reported sunburns at 12 months in Australian adults with no history of melanoma. This was alongside genetic counselling and educational materials on skin cancer prevention and early detection. However, the economic impact of this approach was unclear. This study aimed to determine the cost-effectiveness of the program to prevent melanoma and KC. Methods: A decision-analytic Markov model was developed to simulate the lifetime cost-effectiveness of personalized genomic risk provision compared with standard prevention advice alone, from a health system perspective. We used data from the Melanoma Genomics Managing Your Risk Study Randomized Control Trial. Traditional risk was measured by a validated melanoma risk prediction model involving hair color, nevus density, history of non-melanoma skin cancer, family history of melanoma, level of sunbed sessions. Quality-adjusted life years (QALY) gained was the primary outcome measure used to estimate an incremental cost-effectiveness ratio (ICER). Both deterministic and probabilistic sensitivity analyses (PSA) were undertaken. Results: The cost of the genomic testing and risk counselling program was AUD$189 (USD$132) per participant. Genomic risk provision targeting high-traditional risk individuals was the most cost-effective lifetime strategy with an ICER of AUD$23,033 (USD$16,059) per QALY gained and an 80% probability of being cost-effective at a willingness-to-pay threshold of AUD$50,000, compared with standard preventive advice (Table). When genomic risk provision was extended to low-traditional risk groups the ICER was $43,746 (USD30,500) per QALY gained with a 45% probability of being cost-effective. Conclusions: Genomic risk provision targeted to individuals at high-traditional risk of melanoma is a cost-effective strategy for the prevention of melanoma and KCs. Long-term sustainability of the program’s effect should be examined in future research. Clinical trial information: ACTRN12617000691347.