This case-control study investigates the potential chemoprophylactic properties of non-steroidal anti-inflammatory drugs (NSAIDs) on the incidence of cutaneous melanoma (CM). Data were extracted from the Dutch PHARMO pharmacy database and the PALGA pathology database. Cases had a primary CM between 1991 and 2004, were >= 18 years, and were observed for 3 years in PHARMO before diagnosis. Controls were matched for date of birth, gender, and geographical region. NSAIDs and acetylsalicylic acids (ASAs) were analyzed separately. Adjusted odds ratio (OR) and 95% confidence interval (CI) were calculated using multivariable logistic regression, and the results were stratified across gender. A total of 1,318 CM cases and 6,786 controls were eligible to enter the study. CM incidence was not significantly associated with ever ASA use (adjusted OR: 0.92, 95% CI: 0.76-1.12) or ever non-ASA NSAID use (adjusted OR: 1.10, 95% CI: 0.97-1.24). However, continuous use of low-dose ASAs was associated with a significant reduction of CM risk in women (adjusted OR: 0.54, 95% CI: 0.30-0.99) but not in men (OR: 1.01, 95% CI: 0.69-1.47). A significant trend (P = 0.04) from no use, non-continuous use to continuous use was observed in women. Continuous use of low-dose ASAs may be associated with a reduced incidence of CM in women, but not in men.