The authors conducted a nested case-control study of serum inflammatory markers and risk of symptomatic benign prostatic hyperplasia (BPH), using data from the placebo arm of the Prostate Cancer Prevention Trial (1993-2003). Incident BPH (n = 676) was defined as treatment, report of 2 International Prostate Symptom Score (IPSS) values >14, or 2 increases of > or = 5 from baseline values with at least one value > or = 12. Controls (n = 683) were men who reported no BPH treatment or IPSS values >7 over the 7-year trial. Baseline serum was analyzed for C-reactive protein, tumor necrosis factor alpha (monomer), soluble tumor necrosis factor receptors I and II (sTNF-RI and sTNF-RII), interleukin 6, and interferon gamma. Controlled for age and race, a high C-reactive protein concentration was associated with increased BPH risk (for quartile 4 vs. quartile 1, odds ratio (OR) = 1.40, 95% confidence interval (CI): 1.04, 1.88); this was attenuated after control for body mass index (OR = 1.30, 95% CI: 0.95, 1.75). Low sTNF-RII and high interleukin 6 concentrations were associated with increased BPH risk (for quartile 4 vs. quartile 1, sTNF-RII: OR = 0.61, 95% CI: 0.46, 0.82; interleukin 6: OR = 1.79, 95% CI: 1.32, 2.42); these associations were only in men aged <65 years. Results suggest that systemic inflammation or lower levels of soluble receptors that bind inflammatory cytokines increase BPH risk.