The O’Leary-Sant Interstitial Cystitis Symptom Index (ICSI) has been proposed as a treatment outcome measure in interstitial cystitis (IC). The psychometric properties of the ICSI were assessed for reliability and validity in a randomized, double-blind clinical study of 300, 600, and 900 mg daily dose of pentosan polysulfate sodium (PPS) in patients with IC. The ICSI contains 4 items that measure urgency and frequency of urination, nighttime urination, and pain or burning. The ICSI index score is the sum of the item scores (range: 0–20). ICSI scores were obtained at baseline, 4, 8, 12, 16, 24, and 32 weeks of treatment. Patients’ overall ratings of improvement of symptoms (PORIS) scores evaluating improvements in pain, urgency, and overall IC symptoms were also collected except at baseline. A total of 376 patients were included in the analysis. Psychometric properties evaluated included variability (range), test–retest reliability (intraclass correlation coefficient [ICC]), internal consistency (the Cronbach ⍺), construct validity (convergent, discriminant), responsiveness, and clinically meaningful change. The ICSI items and index score had good variability and test–retest reliability. The ICSI demonstrated internal consistency reliability and was responsive to change. Participants indicating a 75% improvement in PORIS had a 48% mean reduction in the ICSI score, while participants reporting 100% improvement in PORIS had a 77% mean reduction in the ICSI score. The ICSI is a valid, reliable, and responsive measure of change in IC symptoms. This outcome measure should be utilized in future treatment outcomes studies in IC.