BACKGROUND: More than 180 different types of therapy have been used in the treatment and management of painful bladder syndrome/interstitial cystitis (PBS/IC), yet evidence from clinical trials remains inconclusive. This study aimed to evaluate the efficacy of pharmacologic approaches to PBS/IC, to quantify the effect size from randomized controlled trials, and to begin to inform a clinical consensus of treatment efficacy for PBS/IC. METHODS: We identified randomized controlled trials for the pharmacologic treatment of patients with PBS/IC diagnosed on the basis of National Institute of Diabetes and Digestive and Kidney Diseases or operational criteria. Study limitations include considerable patient heterogeneity as well as variability in the definition of symptoms and in outcome assessment. RESULTS: We included a total of 1470 adult patients from 21 randomized controlled trials. Only trials for pentosan polysulfate sodium had sufficient numbers to allow a pooled analysis of effect. According to a random-effects model, the pooled estimate of the effect of pentosan polysulfate therapy suggested benefit, with a relative risk of 1.78 for patient-reported improvement in symptoms (95% confidence interval, 1.34-2.35). This result was not heterogeneous (P = .47) and was without evidence of publication bias (P = .18). Current evidence also suggests the efficacy of dimethyl sulfoxide and amitryptyline therapy. Hydroxyzine, intravesical bacille Calmette-Guérin, and resiniferatoxin therapy failed to demonstrate efficacy, but evidence was inconclusive owing to methodological limitations. CONCLUSIONS: Pentosan polysulfate may be modestly beneficial for symptoms of PBS/IC. There is insufficient evidence for other pharmacologic treatments. A consensus on standardized outcome measures is urgently needed.