OBJECTIVES. This study tests the hypothesis that fluoride exposure in a nonoccupational setting is a risk factor for childhood osteosarcoma. METHODS. A population-based case-control study was conducted among residents of New York State, excluding New York City. Case subjects (n = 130) were diagnosed with osteosarcoma between 1978 and 1988, at age 24 years or younger. Control subjects were matched to case subjects on year of birth and sex. Exposure information was obtained by a telephone interview with the subject, parent, or both. RESULTS. Based on the parents' responses, total lifetime fluoride exposure was not significantly associated with osteosarcoma among all subjects combined or among females. However, a significant protective trend was observed among males. Protective trends were observed for fluoridated toothpaste, fluoride tablets, and dental fluoride treatments among all subjects and among males. Based on the subjects' responses, no significant associations between fluoride exposure and osteosarcoma were observed. CONCLUSIONS. Fluoride exposure does not increase the risk of osteosarcoma and may be protective in males. The protective effect may not be directly due to fluoride exposure but to other factors associated with good dental hygiene. There is also biologic plausibility for a protective effect.