Contralateral prophylactic mastectomy (CPM) and bilateral prophylactic mastectomy (BPM) markedly decrease the possibility of new breast cancer (BC) ipsilateral to the prophylactic mastectomy (PM). Given its relative infrequency, little is known about the clinical characteristics, presentation, and management of BC after PM. Between 1960 and 1993, 1065 women underwent BPM and 1643 women with unilateral BC treated with therapeutic mastectomy underwent CPM at our institution. Medical records were reviewed, and study-specific questionnaires were sent to all women. BC after PM included locoregional invasive BC or ductal carcinoma in situ ipsilateral to the PM. BC developed ipsilateral to the PM in 25 patients (13 after BPM; 12 after therapeutic mastectomy and CPM). Median follow-up after PM was 22 years (range 3-34 years). Presentations included clinically isolated local disease in 17 patients (68%); disease limited to the axilla without evidence of local primary disease in 4 (16%); synchronous local and axillary disease in 1 (4%); and synchronous local disease and distant metastases in 3 (12%). The 17 patients presenting with isolated local disease were most commonly managed with completion or redo mastectomy (65%) or local excision (29 %), followed by consideration of adjuvant therapy. The 5-year disease-free survival estimate was 69% (95% CI 52-94%) for the 22 patients who had isolated locoregional BC after PM and were treated with curative intent. Although rare, BC after PM can occur. The most common presentation, disease localized to the mastectomy site, can be managed with resection and consideration of adjuvant therapy.