The issue of whether multifocal breast cancer represents intramammary spread from a single primary tumor or multiple synchronous tumors remains unresolved. We have used a series of immunocytochemical markers, B72.3, DF3, c-erbB-2, SP-1, CEA, and p53, to attempt to answer this question. Of 24 cases with separate discrete synchronous tumors in the same breast, 10 were histologically and immunocytochemically identical, five were histologically similar but immunocytochemically different, two were histologically different but immunocytochemically identical, and in seven cases the tumors were different both histologically and immunocytochemically. In seven of the 24 cases lymph nodes containing metastatic tumor were also available; in each instance, the immunoreactivity of the metastasis was similar to one or other of the tumors in the breast. This study indicates that multifocal breast cancer may result from either intramammary spread from a single primary tumor or multiple synchronous primary tumors.