Objective: Markers of neuroinflammation, including activated microglia and increased levels of circulating proinflammatory cytokines, have been observed in the brains and CSF of patients with Parkinson disease ( PD). Yet the link between anti-inflammatory agents and PD in humans remains uncertain, despite indications that neuroinflammation may contribute to cell death in the PD brain and experimental evidence of anti-inflammatory agents such as nonsteroidal anti-inflammatory drugs ( NSAIDs) exerting neuroprotective effects in animal models. Methods: Using a population-based approach, we studied NSAID use among 293 incident idiopathic PD cases and 286 age-, race-, and gender-matched controls from three rural California counties. Results: Our data suggested a decreased risk of PD among regular ( >= 2 pills/week for at least 1 month) aspirin NSAID users ( OR, 0.80; 95% CI, 0.56 to 1.15). A stronger protective effect was observed for regular nonaspirin NSAID users ( OR, 0.52; 95% CI, 0.35 to 0.79), particularly those who reported 2 or more years of use ( OR, 0.44; 95% CI, 0.26 to 0.74). The aspirin effect estimates differed by gender, showing a protective effect only in women, especially among long term ( >= 24 months) regular users ( OR, 0.51; 95% CI, 0.26 to 1.02). Conclusion: Our study contributes to the growing body of literature suggesting a protective role for nonsteroidal anti-inflammatory drugs ( NSAIDs) in Parkinson disease ( PD). Given our results and the biologic plausibility of a neuroprotective function for NSAIDs there is a pressing need for further studies elucidating the protective role such drugs may play in PD.