Objective: Statins have several pleiotropic effects, but the literature regarding the possible relationship between use of statins and outcomes in knee osteoarthritis (OA) is limited. The aim of this study was to investigate whether statin use is associated with a lower risk of radiographic OA (ROA), radiographic symptomatic knee OA, and pain in North American individuals. Methods: A total of 4,448 community-dwelling adults from the Osteoarthritis Initiative were followed for 4 years. Statin use (including the time from baseline and the type of statin) was defined through self-report information and confirmed by a trained interviewer. Knee OA outcomes included incident ROA, symptomatic knee OA (new onset of a combination of a painful knee and ROA), and knee pain worsening (i.e., a Western Ontario and McMaster Universities Osteoarthritis Index difference between baseline and each annual examination ≥14%). Results: At baseline, 1,127 participants (25.3% of the total population) used statins. Based on a multivariable Poisson regression analysis with robust variance estimators, any use of statins was not associated with a lower risk of pain worsening (relative risk [RR] 0.97, 95% confidence interval [95% CI] 0.93-1.02), incident ROA, or symptomatic knee OA. However, statin use for more than 5 years (RR 0.91, 95% CI 0.83-0.997) and use of atorvastatin (RR 0.95, 95% CI 0.91-0.996) were associated with a reduced risk of developing pain, while rosuvastatin use was associated with a higher risk (RR 1.18, 95% CI 1.12-1.24). Analysis with adjustment for the propensity score confirmed these findings.