Thrombotic thrombocytopenic purpura (TTP) is a potentially life-threatening thrombotic microangiopathy (TMA) that needs prompt identification and treatment. Disseminated malignancy-related TMA can potentially be misdiagnosed as TTP, and patients may be inappropriately subjected to therapeutic plasma exchange (TPE) with serious implications. Likewise, the presence of a concurrent cancer diagnosis in a patient with microangiopathic hemolytic anemia and thrombocytopenia may lead to suspicion of disseminated malignancy as the cause, delaying the TPE with serious outcomes. Testing for ADAMTS13 activity is diagnostic of TTP, but the results may take time. This poses a diagnostic and therapeutic dilemma that includes weighing the benefits of TPE for treating TTP and cancer treatment. We describe a rare case of immune-mediated TTP in a patient concurrently diagnosed with metastatic renal cell cancer. To our knowledge, this is the first case of TTP reported in patients with metastatic renal cell carcinoma (RCC) in a non-treatment-naive patient.