e12524 Background: We observed an increased incidence of severe skin and nail infections in HER2 positive patients whose treatment regimens included pertuzumab to trastuzumab-based chemotherapy; a previously unrecognized toxicity. Methods: We developed a registry for patients (pts.) who were identified by their treating physician to have severe skin/nail infections attributed to this dual HER2-directed treatment. A single infectious disease specialist (SD) oversaw the attribution of infection to drug or non-drug. Physicians were encouraged to assess quantitative immunoglobulins. Results: To date, 44 women were identified to have 62 individual episodes of infection, often at more than one site. Treatment was given as neoadjuvant therapy -24, as adjuvant therapy - 6, and for metastatic disease -14. The median age was 57 (Range 25-73); 24 received pertuzumab, trastuzumab, carboplatin, and docetaxel (PTCH); 22 pertuzumab, trastuzumab, and a taxane; 2 were on pertuzumab and trastuzumab alone. Folliculitis of the scalp, abdomen, chest wall and/or buttocks was observed in 31 patients; abscesses developed in 15;6 required surgical interventions. Paronychial infections involving one to 16 digits were observed in 6, 3 of whom required surgical intervention. With the exception of 2 pts, all had adequate WBCs. Cultures were obtained in 20 pts., and identified MSSA in 8, MRSA in 5, and Streptococcal species in 3. Two pts. with cellulitis had negative cultures; 1 pt. was cultured after initiation of antibiotics, and 1 pt. died of gram positive cocci sepsis on cycle 2 day 7 of PTCH. Her WBC on day 1 was 13.0, and she received pegfilgrastim on day 2. Immunoglobulins were found to be low in 16 of 29 (41%) women tested. In the absence of culture data, infections were managed with cephalexin, doxycycline, or topical antibiotics. The majority of patients continued on chemotherapy, but pertuzumab was deleted from the regimen in 2 pts. Conclusions: We continue to see a significant increase in gram positive invasive skin and nail infections in women with HER2 positive breast cancer treated with pertuzumab and trastuzumab-based regimens. Low levels of quantitative immunoglobulin in select patients suggest a possible mechanism.