Bupropion is an antidepressant drug also used as a smoking cessation aid, which inhibits norepinephrine and dopamine re-uptake. Given its pharmacological properties, it has been associated with reports on psychosis and acute delirious episodes. Case We report the case of a patient with schizoaffective disorder who developed two psychotic episodes respectively after a four and a two-day administration of sustained-release (SR) bupropion at a dose of 150 mg/day. To our knowledge, this is the first reported case of involuntary rechallenge with bupropion SR during a smoking cessation program. Conclusion There is a serious risk of incorrectly identifying bupropion as only a therapy for nicotine withdrawal without taking the precaution of exploring possible psychiatric co-morbidity with addiction. Our case illustrates the problem.