To examine the effect of cancer histopathology on the relationship between estrogen-replacement therapy (ERT) use and breast cancer risk, we performed a case-control study of 109 postmenopausal women 45 years or older with in situ or invasive breast cancer matched to 545 controls. When in situ and invasive tumors were combined, the overall odds ratio (OR) describing the association between ERT use and breast cancer risk was not statistically significantly elevated (adjusted OR = 1.48, 95% confidence interval [CI] = 0.89-2.47). When the analyses were confined to women with invasive disease, risk estimates were uniformly higher (adjusted OR = 1.85, 95% CI = 1.00-3.45). In contrast, the overall estimate for the relationship between ERT use and in situ breast cancer was close to 1 (adjusted OR = 1.08, 95% CI = 0.42-2.77). The positive association between ERT use and invasive breast cancer we observed, and the lack of association in women with in situ disease, may represent a distinct biological difference or may be related to the small sample size of our study.