The authors conducted a cohort study of nonsteroidal antiinflammatory drug (NSAID) use and risk of symptomatic benign prostatic hyperplasia (BPH), using data from 4,735 men without BPH at baseline in the placebo arm of the Prostate Cancer Prevention Trial (1993-2003). Incident BPH (n = 471) was defined as medical or surgical treatment or at least 2 International Prostate Symptom Score (I-PSS) values greater than or equal to 15. Proportional hazards models using time-dependent exposure for NSAID use were employed to estimate covariate-adjusted associations of NSAID-related medical conditions and NSAID use with BPH risk. Arthritis, other inflammation-related musculoskeletal conditions, and headaches were associated with increased BPH risk (hazard ratio (HR) = 1.77 (95% confidence interval (CI): 1.37, 2.29), HR = 1.57 (95% CI: 1.14, 2.17), and HR = 1.40 (95% CI: 1.09, 1.80), respectively). Use of any NSAID, use of aspirin, and use of nonaspirin NSAIDs were associated with significant increases in BPH risk (HR = 1.21 (95% CI: 1.01, 1.46), HR = 1.20 (95% CI: 1.00, 1.45), and HR = 1.34 (95% CI: 1.07, 1.69), respectively). Control for indications for NSAID use, including baseline I-PSS, attenuated the associations slightly, but all became nonsignificant. Among men with no indications for NSAID use, the hazard ratio for any NSAID use was 1.06 (95% CI: 0.82, 1.38). The modest associations of NSAID use with BPH risk in this cohort were probably due to confounding by indication, and NSAID use was not associated with BPH risk.