Tumor lysis syndrome (TLS) is a hemato-oncological emergency characterized by metabolic and electrolyte imbalances which are associated with disintegrating tumor cells. The syndrome is frequently observed when starting cytotoxic treatment of hematological malignancies, while the incidence of spontaneous tumor lysis prior to the start of tumor therapy is rare. Here, we present a case of spontaneous TLS in a male patient who was referred with unspecific symptoms and suspected metastatic malignancy. He developed acute renal failure before the diagnosis of a high-grade B-cell lymphoma (double hit lymphoma) and start of therapy. Although the course of TLS would have required intensive care, the patient rejected such treatment for personal reasons and died soon after the discontinuation of therapy. The case emphasizes the life-saving relevance of early detection and appropriate treatment of TLS. It also demonstrates the importance of actively screening for TLS, primarily in patients with malignant diseases and high tumor load, even if they are not receiving cytotoxic therapy.