Tamoxifen, a nonsteroidal antiestrogen, is the endocrine therapy of choice for all stages of breast cancer. Because tamoxifen is well tolerated and has minimal side effects, it is currently being evaluated in large scale trials as a chemopreventive agent for women at risk for developing breast cancer. The potential adverse effects of tamoxifen, specifically the development of proliferative lesions of the endometrium, coupled with the prospect of its wider use, places new emphasis on recognizing tamoxifen-associated histologic and cytologic changes in the female genital tract. The current study evaluated cervical smears from 52 breast cancer patients treated with tamoxifen compared with 21 smears from breast cancer patients who had not received tamoxifen. Cytologic diagnoses were classified according to the Bethesda system. The presence of blood, inflammation, and hormonal effect were also assessed. No squamous intraepithelial lesions were identified. A total of 21 of 38 smears (55%) from patients receiving tamoxifen alone and 11 of 14 smears (78%) from women who received tamoxifen in combination with adjuvant cytotoxic chemotherapy showed atypias compared with only 6 of the 21 breast cancer patients (28%) who did not have hormonal therapy. The number of smears showing atypia was equally divided into changes interpreted as benign reactive and atypical squamous cells of undetermined significance (ASCUS). Of the 19 patients whose smears were classified as ASCUS, 13 patients had a subsequent cervical biopsy and none showed dysplasia or diagnostic human papilloma virus changes. Tamoxifen therapy was not associated with an increase in the presence of blood or inflammation, and no discernible alteration in the hormonal state was seen in the cervical smears. We conclude that the use of tamoxifen may be associated with benign squamous atypia in cervical smears and that the atypia is not associated with intraepithelial lesions.