Approximately half the patients with diffuse or follicular large-cell or mixed large- and small-cell lymphoma enter a prolonged remission or are cured after receiving combined-drug therapy. It has been unclear, however, why the other half do not respond. We evaluated 54 previously untreated patients with diffuse lymphoma and 20 with follicular lymphoma, all of whom had a large-cell component and Stage II through IV disease, subsequently treated with combined chemotherapy. Different recurrent genomic defects were associated with differences in the response to treatment. Among the 54 patients with diffuse lymphoma, all 12 patients with a duplication of chromosome 3p had a complete clinical remission after a median follow-up of 39 months (11 patients survived). In contrast, all seven patients with a duplication of chromosome 2p had a partial response or no response to treatment and a median survival of six months (all died). Among the 20 patients with follicular lymphoma, all 5 patients with duplication 3p or +3 had a complete clinical remission (all survived), and 3 of 4 patients with duplication 2p or +2 had no response or a partial response to treatment and died. Twenty-three patients with B-cell non-immunoblastic lymphoma or follicular lymphoma who had a bcl-2 oncogene rearrangement had a poorer response to therapy (7 of 23 with complete remission) than the patients without bcl-2 rearrangement (21 of 26 with complete remission). We conclude that in large-cell or mixed-cell lymphoma, duplication of chromosome 3p is associated with a relatively good prognosis and duplication of chromosome 2p or bcl-2 oncogene rearrangement is associated with a relatively poor prognosis. Because such multiple recurrent genomic defects are also common in most other types of cancer, they may have general prognostic importance.