Twenty-seven patients with assessable, regionally advanced, or metastatic upper aerodigestive cancer of diverse histology received a combination of mitomycin C, adriamycin, and cis-diamminedichloroplatinum. All patients had previously received extensive surgery and/or radiation therapy. We observed an overall 46% partial response rate (12/26). This included seven of 15 (47%) responders with squamous cell carcinoma. Six of those seven patients responded within the initial month of treatment. For all study participants, the median time to progression and survival was 3.8 months and 7.3 months, respectively. Moderate-to-severe nausea, vomiting, anorexia, and alopecia were the most common toxicities. Myelosuppression (WBC less than 4,100 cells/mm3) and thrombocytopenia (PLTS less than 130,000 cells/mm3) occurred in 100% and 71% of the 21 patients with nadir data recorded, respectively. There were no episodes of sepsis nor did we detect any meaningful impairment in renal function. This regimen is active in the previously treated head and neck cancer patient and can be conveniently administered on an outpatient basis with acceptable and manageable side effects.