The breast is an uncommon site of presentation for primary non-Hodgkin's lymphoma, with prognosis and patterns of relapse still not clearly defined. A retrospective analysis of 21 patients presenting to 2 Australian centers during a 20-year period is presented. All patients were women and had a median age of 62 years. Fifteen patients (71%) had localized disease (12 unilateral and 3 bilateral), and 6 (29%) had regional lymph-node involvement. Histology was predominantly intermediate grade, with diffuse large B-cell lymphoma (DLBL) in 16 cases (76%). The most common treatment program was partial mastectomy followed by chemotherapy and radiation therapy (n = 12). Complete response (CR) to treatment was exhibited in 19 patients (90%), 11 of whom subsequently experienced relapse. Including the 2 patients who failed to exhibit an initial CR, the median time to disease progression was 23.4 months (range, 0-143 months), with a 5-year disease-free survival rate of 38% (+/- 12%). The actuarial median survival of all patients was 3.8 years, with bilateral breast involvement at presentation the only significant prognostic factor. The contralateral breast was the site of initial relapse in 3 patients (17%), all of whom subsequently died of disease. The actuarial rate of central nervous system (CNS) recurrence at 8 years was 39% (+/- 14%), occurring only in patients with diffuse large-cell histology. Our analysis suggests that DLBL presenting in the breast has a poor prognosis and characteristic patterns of failure. Targeted strategies such as CNS prophylaxis and contralateral breast irradiation might therefore improve prognosis and should be prospectively studied.