A single institution's experience with the treatment of localized primary lymphoma of the breast (PLB) was analyzed to understand the natural history of this disease and to identify major prognostic factors and optimal treatment. A retrospective analysis of 23 previously untreated patients who met the strict criteria of PLB from 1972 through 1994 was undertaken. All pathologic materials were reviewed and classified by the Working Formulation. The Ann Arbor stages (AASs) were: IE, 17 patients; IIE, five patients; IV, one patients (bilateral breast involvement without distant metastasis). Pathologic findings were: low grade, two patients; intermediate grade, 18 patients (17 with diffuse large-cell lymphoma (DLCL)); high grade, two patients; and unclassifiable, one patient. The treatments after biopsy or mastectomy were: radiation alone, two patients; chemotherapy alone, six patients; and combined-modality therapy, 13 patients. Two patients had mastectomy alone. Overall survival (OS) and relapse-free survival (RFS) were calculated actuarially. Univariate analyses were performed with patient age, treatment modality, AAS, size of the primary tumor (T stage), and International Prognostic Index (IPI) for the 17 patients with DLCL to define prognostic factors. The median follow-up for the surviving patients was 78 months (range, 45-220 months). The 5-year OS and RFS were 74% and 73%, respectively for all 23 patients, and 65% and 70%, respectively, for the 17 patients with DLCL. Statistically significant factors for OS for DLCL were AAS and IPI. Statistically significant factors for RFS were AAS and T stage. With modern staging evaluation and multiagent combination chemotherapy, localized primary non-Hodgkin lymphoma of the breast, especially diffuse large-cell type, has a prognosis as favorable as that of other DLCL. Ann Arbor stage was a significant factor for both OS and RFS.