Two observations of severe neuropsychiatric reactions occurring during chemoprophylaxis with mefloquine are reported. The first case regards a 43 years old woman who developed a severe depression with visual and auditive hallucinations and a paranoid delusion. She was treated by clomipramine and risperidone. The second case concerns a 55 years old man who developed an acute psychosis with confusion. He was treated with halopridol during a short time. He presented twice an acute psychosis during a chemoprophylaxis with mefloquine. Several cases of neuropsychiatric side effects with mefloquine chemoprophylaxis or treatment have been described. Authors estimate that one of 250 therapeutic users has severe neuropsychiatric reactions, compared with one of 10,000 to 15,000 in the prophylaxis users. Disorders could last from 15 minutes to several weeks. Women and patients with personal or familial antecedents of psychiatric disorders are more frequently concerned. Alcohol and the association with other antimalarial drugs (like quinine) are two other risk factors. Therefore, some advices may be suggested regarding the use of mefloquine for malaria prophylaxis and treatment.