Colon carcinoma, the second leading cause of cancer-related deaths in the United States, is resistant to chemotherapy in a large majority of cases. Single-agent and combination chemotherapy have failed to prolong survival. New approaches are clearly needed. In experimental models, a steep dose-response curve for colorectal cancer has been demonstrated using various agents. The hematopoietic toxicity of high-dose therapy with these drugs can be circumvented by autologous bone marrow transplantation. We investigated the use of high-dose melphalan with autologous bone marrow rescue in 20 patients with metastatic colon carcinoma. Each patient received melphalan, 180 mg/m2 intravenously (IV), followed eight hours later by bone marrow infusion. Median duration of granulocytopenia (less than 500 neutrophils/microL) was twelve days (range, 5 to 35 days), while transfusion-dependent thrombocytopenia (less than 20,000 platelets/microL) had a median duration of eight days (range, 3 to 23 days). Time to bone marrow engraftment was not affected by prior 5-fluorouracil therapy. Nausea and vomiting occurred in 14 patients but was generally short lived. Mild stomatitis, esophagitis, and diarrhea were common. Severe gastrointestinal (GI) side effects did not occur. One treatment-related death occurred secondary to intramural tumor necrosis, which resulted in massive lower GI bleeding. Complete responses were observed in three patients (15%) and partial responses in six patients (30%), for an overall response rate of 45%. Median survival was 198 days in this group of patients with extensive disease. High-dose melphalan therapy for metastatic colon carcinoma, when used with autologous bone marrow transplantation, appears to achieve a high response rate with tolerable toxicity. Further investigation is needed to define the role of this therapy in the care of advanced colon carcinoma.