Background <p>Piperacillin-tazobactam (PT), a broad-spectrum β-lactam/β-lactamase inhibitor combination, is clinically used to treat infections caused by Gram-positive and Gram-negative aerobic and anaerobic bacteria. While gastrointestinal adverse effects, skin reactions, and fever have been previously reported during PT therapy, its association with periodic fever, leukopenia, and hypokalemia specifically in post-trauma surgical patients has not been documented.</p> Case presentation <p>We report the case of a 55-year-old male trauma patient who received PT for 17 days pre-operatively for suspected infection. He then underwent surgical procedures including rib fracture open reduction and internal fixation, along with thoracic closed drainage. Post-operatively, on day 2, the patient developed periodic fever, occurring specifically between 20:00 and 23:00 hours each night, with normal daytime temperatures. Concurrently, during PT administration, the patient exhibited leukopenia and hypokalemia. Notably, cessation of PT led to an immediate resolution of the periodic fever, gradual normalization of leukocyte counts, and restoration of potassium levels. Although PT can cause fever, diagnosis can be challenging in the post-operative setting due to the potential for confounding factors.</p> Conclusions <p>This case suggests that in surgical patients presenting with periodic fever, particularly when accompanied by leukopenia and hypokalemia after exposure to PT, the drug should be considered a potential causative agent, even if other post-operative complications are being investigated.</p>