A small number of patients with early stage breast cancer are found on presentation to have two or more separate carcinomas within the breast. To assess the effectiveness of conservative surgery and radiation therapy in these patients we compared treatment outcome among 10 patients with multiple lesions (21 cancers) and 707 patients with single lesions, treated at the Joint Center for Radiation Therapy between 1968-1981. Median follow-up was 64 months and 75 months for the multiple and single lesion groups, respectively. In each patient with multiple lesions, both (or all 3) lesions had similar histologic features. Eight of these ten patients (80%) had an infiltrating ductal carcinoma (IDC) compared to 72% of patients with single lesions. Six of these 8 patients with IDC had at least 1 lesion with an extensive intraductal component (EIC), compared to a 33% incidence of an EIC in solitary lesions. All lesions were grossly excised. Radiotherapy was given to the entire breast in all patients, with the majority also receiving a boost dose to the tumor bed site. Four of the 10 patients with multiple lesions recurred in the treated breast (40%) compared to 77 of the 707 patients (11%) with single lesions (p = 0.019, Fisher exact test). In the six patients with multiple lesions who had an EIC, three developed a local failure. In comparison, 43 of 167 patients (26%) with a single lesion with EIC developed a local failure. In patients with multiple lesions, 0 of 2 with IDC without an EIC, and 1 of 2 with histologies other than IDC had recurrence in the treated breast compared to 19 of the 342 (6%) and 15 of the 198 (8%) patients with single lesions with similar histologic features, respectively (p = NS). These results suggest that the presence of 2 or more separate primary tumors in the breast is associated with a high likelihood of local recurrence after treatment with conservative surgery and radiation therapy, even when all identified tumors are grossly resected. This may reflect the common finding of an EIC in these tumors. We conclude that the use of conservative surgery and radiation therapy for patients with more than one primary cancer in the breast should be considered with caution.