Abstract Background: The presence of macroscopically multiple ipsilateral invasive breast cancer (MMIIBC) has been considered a contraindication for breast conservation. Early series reported high rates of local recurrence. A treatment regimen was developed to accommodate patient requests for breast conservation in MMIIBC. Methods: We reviewed medical records of the 15 MMIIBC patients who underwent partial mastectomy followed by radiation between 1989 and 1997. All patients had 2 or more separate macroscopic tumors greater than 2 mm in diameter. After tumor excision, all specimens were evaluated; the protocol required surgical margins of at least 2 mm. Results: As of June 2000 (median follow-up 76 months), 14 patients (93%) were alive without evidence of disease. One patient died of systemic disease without local recurrence. Conclusions: In selected cases, the combination of breast conservative surgery and radiation therapy with systemic therapy results in acceptable local-regional control. Patients who present with MMIIBC with clear surgical margins should be considered for breast conservation.