Objectives. To study the clinical effect of diagnostic overdistension plus hyaluronic acid (HA) instillations in interstitial cystitis and the association of the clinical response with the intensity of intercellular adhesion molecule (ICAM)-1 expression. HA is an important component in the urothelium. It inhibits adherence of immune complexes to polymorphonuclear cells, leukocyte migration, and aggregation. HA binds to lymphocytes and endothelial cells expressing ICAM-1. Methods. Eleven patients with interstitial cystitis who fulfilled the diagnostic criteria of the National Institutes of Health were selected for the trial. The bladder was distended for 1 minute with a pressure of 80 cm H 2O and biopsies were taken from the petechial areas. The patients were treated with four weekly intravesical HA instillations (40 mg/50 mL NaCl solution). Biopsies were repeated 2 weeks after the instillations. The ICAM-1 intensity was blindly determined in the lymphocytes and endothelial cells of the vessels from the histologic biopsies. A semiquantitative scoring index was used to measure the inflammatory effect of ICAM-1 receptors. Results. In the long-term responders (2 women and 1 man) and short-term responders (5 women), the pretreatment ICAM-1 index was 3.7 (range 3 to 4); it was 1.8 (range 1.5 to 2) in the nonresponders. Two weeks after the final instillation, the index was 3.5 (range 3 to 4) in the long-term responders and 3.4 (range 3 to 4) in the short-term responders; in the nonresponders, it had increased to 2.8 (range 2.5 to 3.5). Conclusions. Increased ICAM-1 intensity was found in patients with interstitial cystitis; it was higher in those who responded to overdistension plus HA instillations. By blocking the ICAM-1 receptors, HA presumably alleviates the inflammatory processes, but repeated instillations are needed to maintain the response.