This case report describes a 92-year old woman presenting with acute confusion and agitation. She was initially diagnosed as having a hyperactive delirium. However, based on the presence of additional and evolving features of twitchiness, reduced coordination, palpitations and headaches, the diagnosis was re-evaluated. The clinical presentation was subsequently recognised as being that of the serotonin syndrome. In this instance, the serotonin syndrome was judged to have arisen from the concurrent use of duloxetine and tramadol. Duloxetine is an antidepressant with serotonergic properties. Tramadol is an analgesic agent with weak opiate agonist receptor effects, and also exerts reuptake inhibition of noradrenaline and serotonin. The patient’s polypharmacy was reviewed, and alongside other general supportive care measures, her symptoms and signs resolved within 48 hours. This report serves as a clinical reminder on the potential pitfalls of polypharmacy in older patients. Delirium is a common presentation in older patients, and on occasions, clearly establishing the underlying causes or risk factors may prove challenging or even elusive. The report prompts clinicians to bear in mind that the presentation and diagnosis of the serotonin syndrome requires a high index of suspicion, and that patients may present atypically. In support of pharmacovigilance reporting, two scales of causality assessment are employed in this case review. The application of these systems exemplifies their potential in promoting and enhancing objectivity when clinicians report suspected adverse drug reactions (ADRs) noted in routine clinical practice.