BACKGROUND: Anecdotal case reports suggest tamoxifen as a possible treatment for retroperitoneal fibrosis, but a systematic assessment of its effect is not available. OBJECTIVE: To describe the course and outcomes of patients with nonmalignant retroperitoneal fibrosis treated with tamoxifen. DESIGN: Prospective, consecutive series. SETTING: Single tertiary care referral center. PATIENTS: 19 patients with nonmalignant retroperitoneal fibrosis treated with tamoxifen from April 1998 through April 2005. INTERVENTION: Tamoxifen, 20 mg orally twice daily. MEASUREMENTS: Clinical improvement, laboratory variables, and follow-up computed tomography (CT) and gallium scan findings. RESULTS: Fifteen patients reported substantial resolution of symptoms after a median treatment duration of 2.5 weeks. Erythrocyte sedimentation rate and C-reactive protein also improved. Gallium scanning at follow-up showed incomplete disappearance of pathologic gallium-67 activity. Repeated CT scanning showed slow but steady mass regression in 14 of 15 clinical responders. Five patients failed treatment, including 1 patient who improved clinically. Disease recurred in 1 patient who responded to reintroduction of tamoxifen. One patient developed reversible hepatitis. LIMITATIONS: This small observational study did not have a control group. CONCLUSION: Tamoxifen may be a viable therapeutic option in the treatment of retroperitoneal fibrosis.