INTRODUCTION AND HYPOTHESIS Dimethyl sulfoxide (DMSO) bladder instillation is a standard therapy for interstitial cystitis (IC); however, there are varying degrees of success. We hypothesize that first-line intravesical therapy with a DMSO cocktail will optimize treatment outcome. METHODS Ninety women with newly diagnosed IC were enrolled consecutively for the treatment. The IC symptom and problem index was used as an outcome measure. RESULTS Six (6.7%) patients dropped out of the treatment due to intolerable bladder irritation. Fifty-five (65.5%) of the remaining 84 patients, who completed the treatment, experienced ≧50% symptomatic improvement. After a regression analysis, three clinical variables were found to affect treatment adversely, i.e., the presence of advanced cystoscopic glomerulations, microscopic hematuria, and urodynamic detrusor underactivity, respectively. CONCLUSIONS Our results suggest bladder instillation with a DMSO cocktail may well be considered as first-line therapy for IC patients. However, there exists a subgroup of nonresponders who may have severe disease.