Background: Patients with stage T3-4 and/or N-positive rectal cancer have a high risk for local recurrence with or without distant metastases. Despite a failure rate of approximately 50%, no standard adjuvant therapy has been defined until recently. Patients and Methods: Between May 1988 and December 1990, 62 patients who underwent potential curative surgery for adenocarcinoma of the rectum were randomly assigned to observation or adjuvant treatment, consisting of perioperative instillation of 20 mg mitoxantrone into the sacral cavity followed by 6 intravenous treatment cycles of leucovorin (200 mg/m2) plus 5-fluorouraciJ (370 mg/m2) on days 1-5 every 4 weeks. Results: After a median follow-up time of 4.5 years, a comparison between the two groups of patients, 57 of whom were eligible, suggested both an improvement in disease-free survival (68% vs. 46%) and a survival advantage (70% vs. 54%) in favor of the adjuvant chemotherapy group. The benefit appears to be greatest in patients with stage II rectal cancer. Particularly striking was the advantage of chemotherapy in decreasing the incidence of locoregional failure: The pelvis with or without distant metastases was the first site of treatment failure in 9 of 15 (60%) patients with documented recurrences in the control group and in 3 of 9 (33%) patients who received additional treatment. Tolerance of chemotherapy in the treatment arm was remarkable, with no evidence of interference with wound healing. Conclusions: Although, due to the small number of patients in this pilot study, no definite conclusions can be drawn, combined local and systemic intravenous chemotherapy seems to represent a potentially effective adjuvant regimen in stage II/III rectal cancer.