Bilateral synchronous breast cancer appears to have a worse prognosis than comparable unilateral breast cancer. HER-2/neu expression in bilateral breast cancer has not been reported. The purpose of this study was to review the characteristics of patients with bilateral synchronous breast cancer and to report the incidence of HER-2/neu overexpression. Between 1984 and 1998, 58 patients were diagnosed with bilateral synchronous breast cancer (defined as both cancers diagnosed within 3 months). The paraffin blocks from both breast specimens were available and immunostained in 21 patients. Of 42 breast specimens, there were 31 invasive carcinomas and 11 noninvasive carcinomas. Of the 21 paired specimens immunostained for HER-2/neu, 11 were invasive cancers in both breasts, nine were invasive cancers in one breast and noninvasive cancers in the other breast, and one was noninvasive cancers in both breasts. Of the 31 invasive carcinomas, HER-2/neu was overexpressed (2-3+) in 22 (71%) and negative (0-1+) in nine (29%). In contrast, 35 of 101 (34.7%) consecutive unilateral invasive breast cancer specimens from our institution overexpressed HER-2/neu. The difference in HER-2/neu overexpression between patients with bilateral synchronous breast cancer and unilateral breast cancer (22/31 v.s. 35/101) was statistically significant (chi square = 11.3, p < 0.001). In cases where both breasts had invasive carcinoma, HER-2/neu overexpression could be either in one (six patients) or both breasts (four patients). The increased mortality of patients with bilateral synchronous breast cancer may be due to the higher incidence of HER-21neu overexpression.