Antihistamines are structurally similar to DPPE, a tamoxifen derivative known to promote tumor growth, and to antidepressants. Animal experiments have linked certain antihistamines and antidepressants with enhanced tumor growth in mice. The few epidemiologic studies examining antihistamine use have not indicated an increased risk. In light of suggestive animal data, structural similarities between antihistamines and DPPE, the widespread use of antihistamines, and the lack of epidemiologic investigation into their use and breast cancer risk, it is important to examine this issue. Female cases aged 25–74 years, diagnosed 1996 to 1998, were identified through the Ontario Cancer Registry. Controls were a random, age-matched sample of women. Cases (n=3,133) and controls (n=3,062) completed a mailed questionnaire that included questions about antihistamines used regularly (undefined), type and duration. Age-adjusted odds ratio (OR) estimates and 95% confidence intervals (CIs) were obtained using logistic regression. Antihistamine users were at no increased risk for breast cancer (OR=0.93, 95% CI: 0.81, 1.06), and no trend in risk was observed for age starting or duration of use. Antihistamine users were at no increased risk. No confounding or effect modification was identified in multivariate modeling. Our findings do not support the hypothesis that women who use antihistamines are at a greater breast cancer risk than those who do not. © 2003 Wiley-Liss, Inc.