We describe a patient who developed hemolysis and methemoglobinemia due to rasburicase (RBU) and was found to have glucose-6-phosphate dehydrogenase (G6PD) deficiency. This is a rare clinical scenario that provides valuable insight into complex diagnosis and management of these life-threatening complications. A 59-year-old male presented to the VA Medical Center with 11 days of epigastric abdominal pain radiating to the back and flank, associated with bloating and lower extremity edema. He was transferred to our facility for percutaneous nephrostomy tube (PCN) placement for renal dysfunction (creatinine 5.5). Computed tomography (CT) scan of the abdomen and pelvis revealed 17 cm retroperitoneal mass engulfing major vessels, involving right renal hilum and ureter with moderate-severe right hydronephrosis. CT guided biopsy of the mass showed intermediate-large malignant cells that were CD20, CD23, BCL2 and BCL6 positive; CD10 and MUM1 negative. Fluorescent in-situ hybridization resulted after discharge to reveal no MYC rearrangement, confirming a diagnosis of diffuse large B-cell lymphoma. Positron-emission tomography CT revealed extensive retroperitoneal lymphadenopathy with pelvic extension into internal and external iliac vessels, encasing aorta, inferior vena cava and anteriorly displacing pancreas and bowel and contiguous involvement of the right kidney with hypermetabolic activity. Moderate right sided pleural effusion was also seen. Creatinine improved with PCN. Uric acid was 10.3 with lactate dehydrogenase (LDH) 953. The patient received RBU for tumor lysis syndrome (TLS). However, pulse oximetry showed an oxygen saturation of 70-80%, though the patient had only mild dyspnea. CT pulmonary embolism (CTPE) showed segmental PE. Therapeutic lovenox was initiated. He underwent thoracentesis with symptomatic improvement but continued to desaturate on pulse oximetry. Arterial blood gas on 100% oxygen via non-rebreather revealed methemoglobin of 4.5% without hypoxemia. LDH worsened to 1668 with low haptoglobin and direct hyperbilirubinemia, suggestive of hemolysis. G6PD was deficient at 0.8 U/g. Treatment was conservative with cautious use of red cell transfusions and supplemental oxygen. Due to hyperbilirubinemia, chemotherapy was started with dose-adjusted etoposide, prednisone, oncovin, cyclophosphamide, and rituximab - with adriamycin withheld upfront. As hemolysis improved the patient received dose-reduced adriamycin. RBU is a recombinant urate oxidase used in managing TLS. It converts uric acid to allantoin, producing hydrogen peroxide, which oxidizes hemoglobin to methemoglobin. G6PD deficiency decreases cellular ability to reduce glutathione and thus detoxify hydrogen peroxide. This causes life-threatening methemoglobinemia and hemolysis. Methylene blue is contraindicated due to the risk of worsening hemolysis in G6PD deficiency. Methemoglobinemia is typically treated in such cases with exchange transfusion or hyperbaric oxygen therapy.