This study was designed to determine response, outcome, and patterns of failure of patients with non-Hodgkin's lymphoma who presented with a testicular mass. Consecutive patients presenting to M.D. Anderson Cancer Center between 1969 and 1999 treated with doxorubicin-based regimens and with radiotherapy and/or intrathecal therapy were considered for this study. We identified 43 patients whose median age was 61 years. Ann Arbor stage (AAS) was I in 22 patients, II in 7 patients, III in 1 patient, and IV in 13 patients. All 43 patients had intermediate-grade lymphomas according to the Working Formulation, and all 31 tumors assessed immunophenotypically were large B-cell lymphoma according to the World Health Organization classification. The International Prognostic Index score was > or = 2 in 18 patients (42%). Thirty-four patients achieved complete remission, 19 of whom relapsed, and 5 failed initial therapy. At 10 years, progression-free survival (PFS) was 20% +/- 9% and survival was 33% +/- 9%. Progression-free survival for patients with AAS I/II vs. III/IV was 36% +/- 13% vs. 0%, respectively (P = 0.004). At 10 years, the actuarial probability of failure in the central nervous system was 34% +/- 9% and was 21% +/- 9% in contralateral testis. Using the intent-to-treat method, patients receiving cyclophosphamide/doxorubicin/ vincristine/prednisone (CHOP), with additional scrotal radiotherapy and intrathecal methotrexate, had a 5-year PFS of 91% +/- 9% vs. 30% +/- 15% vs. 41% +/- 12% for those receiving only one or neither of these additional modalities (P = 0.053). Doxorubicin-based regimens alone appear unable to cure most patients with lymphoma involving the testis, but CHOP with prophylactic intrathecal therapy and adjuvant scrotal radiotherapy appears promising. This should be confirmed with prospective clinical trials and longer follow-up.