BACKGROUND This study relates our experience in the diagnosis and treatment of a rare clinical entity, non-Hodgkin's primary lymphoma of bone. METHODS Seventeen cases of patients with primary lymphoma of bone diagnosed and treated at a single institution between 1975 and 1992 are reviewed. Ten patients received combined-modality therapy, consisting of an anthracycline-containing combination chemotherapy (CT) regimen, followed by adjuvant radiotherapy (RT) to the primary site of disease. Five patients were treated with CT alone; one patient received RT alone; and one patient was treated with CT after emergency RT for spinal cord compression. RESULTS Thirteen patients presented with Stage I disease, two with Stage II; and two with Stage IV disease (multiple bony sites only). Thirteen patients had an intermediate-grade diffuse large cell lymphoma; two had an intermediate-grade mixed small and large cell lymphoma; and two had a high-grade lymphoma (one immunoblastic and one small non-cleaved cell lymphoma). The overall response rate was 94% (18% complete response, 58% partial response 1, and 18% partial response 2). Thirteen patients are alive and disease-free at a median of 29 months; 10 of these received CT+RT, and 3 received CT alone. Three patients have died; one of these received CT+RT and one CT alone, and one relapsed immediately after CT. One patient, who was initially treated with RT and then with CT+RT after relapse, was lost to follow-up 40 months from the start of treatment. CONCLUSIONS Because experience in the literature suggests a 50% distant relapse rate in primary lymphoma of bone treated with RT alone, our policy is to treat all patients with combined-modality therapy (CT+RT). However, only a Phase III randomized, controlled clinical trial will determine whether CT+RT is superior to either modality alone.