Varenicline is a drug that has been developed to help people stop smoking . Results regarding its efficacy are promising. The safety of the drug, however, is controversial when used for patients with mental illnesses because it can have neuropsychiatric side-effects. Although Dutch guidelines and the ‘Farmacotherapeutisch Kompas’ include warnings about the use of varenicline by people with severe mental illness, the drug is still being prescribed for this group of patients. This is not without risk. We illustrate this point by focusing on two patients with bipolar disorder who developed manic symptoms while using varenicline. We discuss relevant literature and make recommendations.