Objective: Because anti-inflammatory drugs may delay cognitive decline and influence brain metabolism in normal aging, the authors determined the effects of the cyclooxygenase-2 inhibitor, celecoxib, on cognitive performance and regional cerebral glucose metabolism in nondemented volunteers with mild age-related memory decline. Design: Randomized, double-blind, placebo-controlled, parallel group trial with 18-months of exposure to study medication. Setting: University research institute. Participants: Eighty-eight subjects, aged 40 -81 years (mean: 58.7, SD: 8.9 years) with mild self-reported memory complaints but normal memory performance scores were recruited from community physician referrals, media coverage, and advertising. Forty subjects completed the study. Interventions: Daily celecoxib dose of 200 or 400 mg, or placebo. Main Outcome Measures: Standardized neuropsychological test battery and statistical parametric mapping (SPM) of FDG-PET scans performed during mental rest. Results: Measures of cognition showed significant between-group differences in executive functioning (F อ1, 30อ ฯญ 5.06, p ฯญ 0.03) and language/semantic memory (F อ1, 31อ ฯญ 6.19, p ฯญ 0.02), favoring the celecoxib group compared with the placebo group. Concomitantly, FDG-PET scans demonstrated bilateral metabolic increases in prefrontal cortex in the celecoxib group in the vicinity of Brodmann's areas 9 and 10, but not in the placebo group. SPM analyses of the PET data pooled by treatment arm corresponded to a 6% increase in activity over pretreatment levels (p ฯฝ0.01, after adjustment for multiple comparisons). Conclusions: These results suggest that daily celecoxib use may improve cognitive performance and increase regional brain metabolism in people with age-associated memory decline.