E22543 Background: Angiosarcoma (AS) is a rare endothelial malignancy with only 2–3 new cases per one million diagnosed yearly but is among the most aggressive soft tissue sarcomas. Some cutaneous angiosarcomas may have a mutational landscape similar to UV light exposed melanoma. These findings offer a rationale for the early limited evidence of checkpoint inhibitor activity in cutaneous angiosarcomas. Methods: This is a retrospective review of patients with locally advanced or metastatic angiosarcoma, who were treated with checkpoint inhibitors at our institution. Descriptive statistics were used to analyze our findings. Results: Since 2016, we have treated seven angiosarcoma patients with checkpoint inhibitors either in the context of clinical trials or off label [Pembrolizumab + Axitinib (NCT02636725; n = 1), a CTLA-4 inhibitor (NCT02694822; n = 2), Pembrolizumab (n = 4)]. Five patients had cutaneous AS, one primary breast AS and one radiation associated breast AS. The average age was 66 years old and 5/7 (71%) patients were females. All patients had received prior systemic therapies (range 1-7, mean 3) and 2/7 (29%) patients had metastatic disease at the time of treatment. The mean number of checkpoint inhibitor doses was 6. At twelve weeks, 5/7 patients (71%) had partial response, by RECIST, of their lesions either on imaging or clinical exam and two (29%) had progressive disease. 6/7 patients are alive to date and, thus far, 3/7 patients (43%) progressed (median 3.4 months)- one achieved partial response after pembrolizumab was switched to ongoing Nivolumab/Ipilimumab, one died of progressive disease at 31 weeks (primary breast AS) and one was placed on subsequent therapy. No patient experienced any toxicities more than grade 2. Conclusions: This is a single institution, retrospective review of patients with AS treated with checkpoint inhibitors, first reported in the literature. Checkpoint inhibitors may be an effective and safe treatment option for this aggressive sarcoma. Prospective clinical trials are needed to systemically study this effect.