3144 Background: Radiotherapy (RT) potentiates immune-mediated responses against tumor antigens, an effect that is enhanced by checkpoint inhibitors (CPIs) and may hold therapeutic promise. However, the mechanisms underlying this abscopal effect can theoretically increase the rate of immune-mediated adverse events (irAEs). We estimated the incidence of irAEs in a single-institution cohort treated with concomitant RT and immunotherapy. Methods: We retrospectively screened 731 patients that received RT and CPIs at our institution. Patients diagnosed with melanoma or Merkel cell carcinoma (MCC) who underwent RT concurrently or within 30 days of CPI administration were eligible. A radiation period (RP) comprised the interval between the first and last treatment days (≤90 days); a patient could contribute multiple RPs. Data on new irAEs diagnosed within 3 months after RT and relevant demographic and clinicopathologic variables were collected; univariate analysis was performed with the chi-squared test. Results: 35 patients (23 male, 12 female) contributed 43 RPs; mean age was 65.5 years (range: 39-90). Five had MCC, and 30 had melanoma (24 cutaneous, 1 uveal and 5 urogenital melanomas). PD-1 inhibitors were most commonly employed (22 RPs), followed by ipilimumab-nivolumab (14 RPs), ipilimumab (4 RPs), and avelumab (3 RPs). CPIs were administered concurrently with RT in 32 RPs and sequentially in 11 RPs. Fourteen RPs comprised intracranial radiation. Importantly, 45.7% of patients (16/35) experienced irAEs, which manifested within a month of RT in 25.7% (9/35). Four patients experienced grade ≥3 irAEs leading to hospitalization; one died of respiratory failure after developing pneumonitis. On univariate analysis, no significant association between tumor type, CPI regimen, concurrent RT, intracranial vs. extracranial RT, and irAE incidence was noted. A trend for increased irAEs within the ipilimumab-nivolumab group was observed (p = 0.27). Conclusions: Almost half of patients developed new irAEs following RT, with 25% (4/16) of cases warranting hospitalization; these incidence rates appear to exceed rates from historical data and raise concerns about the additive toxicity of CPIs and RT. Comparison to non-RT cohorts and survival analyses are ongoing.