The primary objective of this study was to evaluate the relative prevalence of estrogen receptor-negative contralateral breast cancer to the first primary cancer and to assess the correlation between the relative overexpression of HER-2/neu in the first primary cancer and contralateral breast cancer. A total of 144 women diagnosed with cancers in contralateral breasts were identified from the Henry Ford Health System tumor registry. Data were retrieved from electronic databases and medical records. Women were dichotomized into users and nonusers of tamoxifen. Hormone receptors were scored as positive or negative. HER-2/neu overexpression, assessed by immunohistochemistry, was scored as 0, 1(+), 2(+), or 3(+). Concordance between hormone receptors of the two cancers was low (kappa = 0.27, p = 0.06). Stratification of women by tamoxifen therapy yielded an almost fivefold increase in the proportion of estrogen receptor-negative cancers among the users, while the proportion of cancers expressing no estrogen receptor remained the same among the nonusers (39.6% versus 40.6%). Matched, archived, paraffin-embedded specimens of the first and contralateral breast cancers were available for 57 women. The correlation between the relative overexpression of HER-2/neu between the first primary and the contralateral breast cancer was 0.4 (p = 0.002). The higher prevalence of estrogen receptor-negative contralateral breast cancer among tamoxifen users concurs with previous reports. The biological mechanism for this observation is not understood; however, it has been proposed that tamoxifen inhibits the proliferation of estrogen receptor-positive breast cancer cells, while estrogen receptor-negative cells may continue to grow because of selective pressure. The correlation between HER-2/neu overexpression in the matched first primary and contralateral breast cancers was statistically significant, suggesting that the diagnosis of HER-2/neu overexpression in contralateral breast cancer is associated with HER-2/neu overexpression in the first primary cancer.