Purpose We retrospectively evaluate the outcome of interstitial cystitis treated with subtrigonal or supratrigonal cystectomy and orthotopic bladder substitution. Materials and Methods Of 22 women and 1 man a mean of 51 years old with interstitial cystitis refractory to conservative therapy 17 were treated with subtrigonal cystectomy and ureteral reimplantation (group 1), and 6 were treated with supratrigonal cystectomy directly above the ureteral orifices (group 2). Both groups underwent orthotopic bladder substitution with an ileocecal pouch (Mainz pouch I). Results Postoperatively functional capacity significantly increased from a mean plus or minus standard error of mean 46 +/− 5 to 346 +/− 57 ml. in group 1 and 34 +/− 61 to 319 +/− 29 ml. in group 2 (p <0.001). Daytime and nighttime urinary frequency significantly decreased from 24 +/− 2 to 8 +/− 1 and 7 +/− 1 to 2 +/− 1 ml., respectively, in group 1 and 28 +/− 2 to 6 +/− 1 to 1 +/− 1 ml., respectively, in group 2 (p <0.001). At a mean followup of 93.9 months 14 patients in group 1 (82%) are completely symptom-free, and 1 has tolerable residual urinary urgency and suprapubic pain. At a mean followup of 31.5 months all group 2 patients are symptom-free and void spontaneously, whereas 41% of the group 1 patients require self-catheterization after subtrigonal cystectomy. Conclusions For interstitial cystitis refractory to conservative treatment subtotal cystectomy with orthotopic bladder substitution with the ileocecal pouch (Mainz pouch I) is a valid therapeutic option. In this series supratrigonal and subtrigonal cystectomy resulted in similar relief of symptoms but the former appears to provide better functional bladder rehabilitation.