Background : Epidemiologic evidence suggests that exposure to UV radiation plays a significant role in the development of melanoma skin cancers. As early surgical removal of the melanoma is the only effective therapy, current strategies for reducing mortality from melanoma focus on prevention of the disease. Chemical sunscreens protect mice from development of skin cancers that resemble sunlight-induced human squamous cell cancers, but there appears to be a complex relationship between UV radiation exposure and development of melanoma. Purpose: We asked whether common sunscreens would protect mice against UV radiation-induced enhancement of melanoma incidence. Methods: C3H mice were exposed to 4.8 kJ/m 2 UVB from FS40 sunlamps twice a week for 3 weeks. Sunscreens containing 7.5% 2 -ethylhexyl-p- methoxycinnamate, 8% octyl-N-dimethyl-p- aminobenzoate, 6% benzophenone-3, or the oil-in-water vehicle alone were applied to the ears and tails of the mice 20 minutes before irradiation. At various times during and after exposure, we determined UV radiation-induced inflamation by measuring ear swelling. We also examined the ears histologically for UV radiation-induced alterations. One day after the final irradiation, 2.5 ×10 4 syngeneic K1735 melanoma cells were injected into the external ears. Mice were examined weekly for tumor growth for 5–8 weeks after tumor cell injection. Control mice were treated in the identical way except for exposure to UV radiation. Results : The incidence of melanomas was significantly higher in the UV-irradiated mice. All three sunscreens protected against UV radiation-induced ear swelling and clearly diminished histopathologic alterations, including sunburn cell formation, epidermal hyperplasia, and mono-nuclear cell infiltrate in the dermis. However, the sunscreens failed to protect against UV radiation-induced increase in melanoma incidence. The sunscreens or vehicle alone did not significantly alter tumor growth. Conclusions: Protection against sunburn does not necessarily imply protection against other possible UV radiation effects, such as enhanced melanoma growth. Implications: Sunscreen protection against UV radiation-induced inflammation may encourage prolonged exposure to UV radiation and thus may actually increase the risk of melanoma development. These findings suggest that further research on the ability of sunscreens to prevent melanoma is urgently needed. [J Natl Cancer Inst 86: 99−105, 1994].