Patients with advanced lymphoma who relapse from intensive first-line combination chemotherapy generally have a very poor prognosis. The use of investigational drugs which lack cross-resistance to agents commonly used for initial therapy represents an important approach to the management of such patients. Based upon our prior experience, we developed a protocol which employed a combination of three new agents. Mitoguazone (600 mg/m2) was administered on Days 1 and 10; etoposide (100-125 mg/m2) was administered on Days 2, 3, and 4; and gallium nitrate (300 mg/m2/day) was administered as a continuous iv infusion over 24 hours on Days 1-7. Treatment cycles were repeated every 3-4 weeks pending tolerance to toxic reactions. Forty-two patients are evaluable for response (35 with non-Hodgkin's lymphoma and seven with Hodgkin's disease). All patients had received extensive prior treatment (median of two previous chemotherapy regimens). Less than one-half of patients had achieved complete remission (CR) with previous therapy. Twenty-two patients (52%) showed major antitumor responses (five CR, 17 partial). All patients who achieved CR had diffuse large cell lymphoma. Two patients in CR relapsed in the CNS. The median duration of response for patients who achieved partial response was 4 months (range, 1-11+). Major toxic reactions included myelosuppression, optic neuritis, mucositis, and corneal keratitis or conjunctivitis. This combination of experimental agents has major therapeutic activity in patients with advanced, resistant lymphoma. Optimal application of these drugs may be obtained by use as one arm of an intensive program of alternating non-cross-resistant regimens.