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The use of either immune checkpoint blockade or RAF/MEK inhibitors represents standard of care treatment options for metastatic melanoma. Each class of these drugs has distinct response kinetics, adverse effects, and unique clinical challenges. Combination of immune checkpoint blockade and RAF/MEK inhibitors may result in rapid and durable responses, however, the potential adverse effects of such combinations are poorly characterized. Here, we describe the case of a patient with BRAF-mutant melanoma who received an initial infusion of anti-PD-1 therapy while taking RAF/MEK inhibitors and experienced severe acute kidney injury, an otherwise infrequent side effect of any of these drugs alone. Treatment with corticosteroids rapidly reversed this process, indicating an underlying immune-mediated complication. A deeper understanding of potential adverse effects of combination therapies and their potential mechanisms should be carefully considered in the treatment landscape for melanoma and other cancers.