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Drugs can have a wide array of effects on hematological cells, including red blood cells (RBCs), white blood cells (WBCs), and platelets. Drug-induced hemolytic anemia (DIHA) can be explained by three different pathophysiological mechanisms. We present a case of a premature neonate born at 34 weeks gestation who was admitted to the neonatal intensive care unit (NICU). He developed respiratory difficulty with mottled skin and was suspected to have bacterial sepsis due to necrotizing enterocolitis (NEC). The patient was eventually started on a broad-spectrum antibiotic, piperacillin-tazobactam. On day eight, the patient started developing jaundice and his hemoglobin level dropped from 12.1 to 8.2 mg/dL. His direct antiglobulin test (DAT) was strongly positive. The patient was suspected to have DIHA. Piperacillin-tazobactam is a commonly used antibiotic for neonatal sepsis, but its potential to cause DIHA in neonates is not well-established. Our case highlights the importance of considering piperacillin-tazobactam as an unrecognized contributor to neonatal jaundice and a potential cause of DIHA in neonates. Further research is needed to explore the extent of its involvement in this condition. Physicians should be cautious when administering this drug to neonates and be aware of the possibility of hemolysis and jaundice.

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