We have analyzed 25 patients with primary testicular large-cell non-Hodgkin's lymphoma managed at our institution from 1972-1998. The median age was 69 years, with bilateral testicular involvement in 16%. The disease stage was I in 56%, II in 32%, and IV in 12%. Twenty-four patients received further therapy after orchiectomy, including chemotherapy in 18 and radiation therapy in 11 (encompassing regional nodes in 8 and the contralateral testis in 6), with 5 patients receiving both modalities. The complete remission rate was 88%, but a continuous pattern of recurrence is evident up to 10 years, when only 23% of patients are predicted to be in ongoing remission. The dominant sites of first failure were extranodal (91%), with prominent involvement of the contralateral testis and cerebral parenchyma. The 10-year overall survival rate is 32%, and the median overall survival is 4.4 years. Within the entire cohort, adverse prognostic factors for treatment failure were serum albumin < or = to 3.5 g/dL (P = 0.02), advanced age, advanced stage, and lack of anthracycline-containing chemotherapy (each P < or = to 0.3). Among patients with locoregional disease, albumin < or = to 3.5 g/dL (P = 0.08), no anthracycline-containing chemotherapy (P = 0.15), and fewer than 6 cycles of chemotherapy (P = 0.03) remained predictive. Based on this analysis, we are prospectively evaluating a treatment program for patients with testicular non-Hodgkin's large-cell lymphoma comprising (1) 6 cycles of anthracycline-based chemotherapy, (2) prophylactic radiation therapy to the contralateral testis, and (3) central nervous system prophylaxis with both intrathecal chemotherapy and systemic high-dose methotrexate.