Awareness of rare differential diagnoses of common clinical presentations helps promote early detection and prompt management of serious conditions. A 54-year-old man, with an infected non-union following a high tibial osteotomy, presented with an acutely discharging abscess to his proximal tibia. He was generally unwell with aStaphylococcus aureusbacteraemia. The tibia was debrided, CERAMENT G used as dead space management and a spanning external fixator applied. Postoperatively, pregabalin and tapentadol were commenced in addition to amitriptyline and sertraline, which the patient was taking regularly. Overnight, the patient developed hyperthermia, inducible clonus, hyperreflexia, agitation, confusion and rigors. Prompt recognition of the possibility of serotonin syndrome resulted in early cessation of serotonergic medications and a positive outcome. From this case an important message is that fever in a patient taking serotonergic medications should prompt a screening neurological examination. Clinicians should also be wary when patients are commenced on multimodal analgesia, including tapentadol.