Background: Inflammatory breast cancer (IBC) is the most aggressive form of breast cancer with poor prognosis and is often resistant to neoadjuvant systemic therapy with early recurrence and metastases. PD-L1 expression in IBC is moderate to high, and blockade of the PD-1/PD-L1 axis with checkpoint inhibitors has emerged as a promising treatment to enhance clinical response. We examined the efficacy of neoadjuvant nivolumab (anti-PD-1 antibody) with chemotherapy in IBC. Methods: This is an open-label multicohort multicenter study of nivolumab with neoadjuvant chemotherapy in patients with newly diagnosed non-metastatic IBC (n=52). All breast cancer subtypes (ER/PR/HER2) were allowed. Patients received nivolumab 360 mg on day 1 (21-day cycle) x 4 cycles with standard chemotherapy. Cohort 1(HER2-negative) received nivolumab with paclitaxel (80 mg/m²)x12 weeks followed by doxorubicin (60 mg/m²) and cyclophosphamide (600 mg/m²) (AC) x 4 cycles. Cohort 2 (HER2-positive) received nivolumab with taxane (paclitaxel 80 mg/m², docetaxel 75 mg/m², or nab-paclitaxel 100 mg/m²), trastuzumab (8 mg/kg then 6 mg/kg), and pertuzumab (840 mg then 420 mg) x 4 cycles followed by AC x 4 cycles. All patients underwent modified radical mastectomy (MRM) followed by radiation and adjuvant therapy per institutional standard of care. Primary objective was pathologic complete response (pCR) (ypT0/Tis ypN0). Residual Cancer Burden (RCB) was assessed. Secondary objectives were safety/tolerability and invasive recurrence-free interval at 2 years. Breast biopsies, residual tumor tissue, and peripheral blood samples were collected for correlative biomarker testing. PD-L1 expression in tumor tissue will be assessed as a predictive marker. Study was closed after 8 patients were enrolled due to slow accrual. Results: 8 patients were enrolled from June 2019-December 2020. All completed neoadjuvant systemic therapy with nivolumab and none had disease progression. They underwent MRM between January 2020-June 2021. Mean age was 57 years (range 43-74). 4 were HER2-positive, 3 were TNBC, and 1 was HR-positive/HER2-negative. 3 were Caucasian, 2 were Latino, 2 were Black, and 1 was Asian. There was no grade 4 toxicity. Most common grade 3 toxicity was neutropenia (n=3). Immune-related events were diarrhea/colitis (n=2) and elevated liver transaminases (n=1). At time of MRM, 4 patients had pCR, 1 had RCB-I, 2 had RCB-II, and 1 had RCB-III. They remain with no evidence of disease and are in follow-up. Tumor biological correlatives are being performed. Conclusions: Addition of nivolumab to neoadjuvant therapy was tolerable and safe and demonstrated anti-tumor activity in IBC with high pCR rate in this pilot study. This supports further investigation of the role of checkpoint inhibitors in treatment of IBC. Clinical trial information: NCT03742986.