Tumor lysis syndrome (TLS) is an oncological emergency that results from massive cytolysis of malignant cells with a sudden release of their contents into the systemic circulation. TLS was rarely described in patients with malignant melanoma. In this article, we describe two patients with malignant melanoma who developed this syndrome. In one of them, the syndrome occurred spontaneously, and this is the second description of spontaneous tumor lysis in a patient with melanoma. We reviewed the previous patients with melanoma-induced TLS and discussed the manifestations and the pathophysiology of the syndrome in our patients.