Australia has the highest rate of skin cancer in the world. Over 434,000 non melanoma and 10,000 melanoma skin cancers are removed in Australia each year. This costs the Australian health system $300 million annually. Melanoma, the most lethal form of skin cancer, arises from melanocytes. It is postulated that the proliferative response of melanocytes following sun exposure may play a role in melanoma susceptibility. Whether this proliferative response is the same for all people, and whether the effect is modified by topical sunscreens, is unknown. In a clinical trial designed to improve our understanding of the interplay between sun exposure, genetic susceptibility and melanoma risk, we recruited 57 participants and used immunohistochemistry to compare the proliferative response of skin cells in vivo. We found that 14 days after exposure of human skin to 2 MED solar simulated ultraviolet radiation (SS-UVR), there were twice as many epidermal melanocytes compared with unirradiated skin. We observed that sunscreen protected against the proliferative response of skin cells following SS-UVR. This study quantified the proliferative response of melanocytes to SS-UVR among people with different phenotypes and genotypes, and found people carrying germline MC1R variants had a 50% lower melanocyte response 14 days after SS-UVR than people with wild-type MC1R. This study confirms the role of UVR in initiating melanocytic proliferation, demonstrates the effectiveness of sunscreen in preventing these responses, and implicates MC1R as a key mediator in this process.