Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is common, but trial evidence is conflicting and therapeutic options are controversial. To conduct a systematic review and network meta-analysis comparing mean symptom scores and treatment response among α-blockers, antibiotics, anti-inflammatory drugs, other active drugs (phytotherapy, glycosaminoglycans, finasteride, and neuromodulators), and placebo. We searched MEDLINE from 1949 and EMBASE from 1974 to November 16, 2010, using the PubMed and Ovid search engines. Randomized controlled trials comparing drug treatments in CP/CPPS patients. Two reviewers independently extracted mean symptom scores, quality-of-life measures, and response to treatment between treatment groups. Standardized mean difference and random-effects methods were applied for pooling continuous and dichotomous outcomes, respectively. A longitudinal mixed regression model was used for network meta-analysis to indirectly compare treatment effects. Twenty-three of 262 studies identified were eligible. Compared with placebo, α-blockers were associated with significant improvement in symptoms with standardized mean differences in total symptom, pain, voiding, and quality-of-life scores of -1.7 (95% confidence interval CI, -2.8 to -0.6), -1.1 (95% CI, -1.8 to -0.3), -1.4 (95% CI, -2.3 to -0.5), and -1.0 (95% CI, -1.8 to -0.2), respectively. Patients receiving α-blockers or anti-inflammatory medications had a higher chance of favorable response compared with placebo, with pooled RRs of 1.6 (95% CI, 1.1-2.3) and 1.8 (95% CI, 1.2-2.6), respectively. Contour-enhanced funnel plots suggested the presence of publication bias for smaller studies of α-blocker therapies. The network meta-analysis suggested benefits of antibiotics in decreasing total symptom scores (-9.8; 95% CI, -15.1 to -4.6), pain scores (-4.4; 95% CI, -7.0 to -1.9), voiding scores (-2.8; 95% CI, -4.1 to -1.6), and quality-of-life scores (-1.9; 95% CI, -3.6 to -0.2) compared with placebo. Combining α-blockers and antibiotics yielded the greatest benefits compared with placebo, with corresponding decreases of -13.8 (95% CI, -17.5 to -10.2) for total symptom scores, -5.7 (95% CI, -7.8 to -3.6) for pain scores, -3.7 (95% CI, -5.2 to -2.1) for voiding, and -2.8 (95% CI, -4.7 to -0.9) for quality-of-life scores. α-Blockers, antibiotics, and combinations of these therapies appear to achieve the greatest improvement in clinical symptom scores compared with placebo. Anti-inflammatory therapies have a lesser but measurable benefit on selected outcomes. However, beneficial effects of α-blockers may be overestimated because of publication bias.