OBJECTIVE: We explored age-specific and gender-specific effects of fluoride level in drinking water and the incidence of osteosarcoma. METHODS: We used data from a matched case-control study conducted through 11 hospitals in the United States that included a complete residential history for each patient and type of drinking water (public, private well, bottled) used at each address. Our analysis was limited to cases less than 20 years old. We standardized fluoride exposure estimates based on CDC-recommended target levels that take climate into account. We categorized exposure into three groups (<30%, 30-99%, >99% of target) and used conditional logistic regression to estimate odds ratios. RESULTS: Analysis is based on 103 cases under the age of 20 and 215 matched controls. For males, the unadjusted odds ratios for higher exposures were greater than 1.0 at each exposure age, reaching a peak of 4.07 (95% CI 1.43, 11.56) at age 7 years for the highest exposure. Adjusting for potential confounders produced similar results with an adjusted odds ratio for males of 5.46 (95% CI 1.50, 19.90) at age 7 years. This association was not apparent among females. CONCLUSIONS: Our exploratory analysis found an association between fluoride exposure in drinking water during childhood and the incidence of osteosarcoma among males but not consistently among females. Further research is required to confirm or refute this observation.