Serotonin syndrome (SS) is a potentially fatal complication of the combined use of agents that enhance serotonin activity. Bupropion inhibits noradrenaline and dopamine reuptake with milder effects on serotonergic activity. Although regarded as a potential causative agent for SS, no cases have been reported in the medical literature. A 62-year-old woman treated with therapeutic dosages of bupropion and sertraline for depression for the previous 3 weeks presented with upper extremity myoclonic jerks, clumsiness, and gait difficulties with fluctuating symptoms of confusion, forgetfulness, and the alternation of agitation and lethargy. Symptoms were interpreted as an aggravation of depression and venlafaxine was added. The clinical picture progressed to alteration of consciousness and dysautonomia. After admission, medications were discontinued and she was started on cyproheptadine and clonazepam with gradual improvement and complete resolution of symptoms. This is a rare report of SS related to the association of bupropion and selective serotonin reuptake inhibitors (SSRIs). It also illustrates the potential for misinterpretation of the earliest manifestations of SS as signs of aggravation of the patient's underlying condition. The role of bupropion in SS is possibly related to its well-established specific inhibition of the cytochrome P450 2D6 pathway, increasing blood levels of SSRIs and tricyclic antidepressants.