BACKGROUND: The safety and feasibility of ductal lavage (DL), a risk-assessment tool utilizing a minimally invasive technique that permits sampling of breast duct epithelium, performed primarily by a nurse practitioner (NP), was studied prospectively. METHODS: Women at high risk for breast cancer with a normal clinical breast exam and mammogram were enrolled. Nipple aspirate fluid (NAF)-yielding ducts were identified, cannulated, and lavaged primarily by an NP in collaboration with a breast surgeon. Samples with sufficient cellularity were categorized as benign, mild atypia, marked atypia, or malignant. Pain and adverse events were recorded. RESULTS: Thirty-seven women, with a mean age of 51.7 years, were enrolled. Thirty-one (83.8%) women yielded NAF and, of those, 28 (90.3%) had one or more ducts successfully cannulated. Of 65 lavaged ducts in these 28 women, cellularity was adequate for diagnosis in 44 (67.7%) samples. Cytologic findings were as follows: 24 benign, 15 mild atypia, 4 marked atypia, and 1 malignant. The procedure was well tolerated with a mean pain score of 3.2 (SD +/- 1.81). The most frequent adverse event was breast fullness, reported by 44.8% of the women. Two women with marked atypia were evaluated further and found to have intraductal papillomata. The woman with malignant cytology had ductal carcinoma in situ. CONCLUSION: DL is a safe, generally well-tolerated procedure that can be performed successfully by a trained NP.