Recent human epidemiologic studies suggest that non-steroidal anti-inflammatory drugs (NSAIDs) have preventive effects against cancers of the colon, breast, and prostate. Laboratory and animal studies also provide evidence of antineoplastic effects of NSAIDs against a variety of solid tumors, including skin cancer. We studied the effects of NSAIDs on malignant melanoma in women utilizing a case control experimental design involving 110 women with histologically proven malignant melanoma, and 609 female controls frequency matched to the cases on age, and place of residence. We observed a significant decrease in the relative risk (RR) of malignant melanoma with regular intake of common over the counter NSAIDs such as aspirin and ibuprofen (RR = 0.45, 95% CI = 0.22-0.92, p < 0.05). Adjustment for sun exposure did not change the magnitude of the estimate. Our results are the first to show that NSAIDs may have value in the chemoprevention of malignant melanoma.