Mefloquine is an important antimalarial drug for treatment and prophylaxis of chloroquine-resistant malaria. Its use has been associated with neuropsychiatric side-effects. We report a case of paranoid psychosis associated with mefloquine occurring in a remote part of Papua New Guinea. Adverse reactions and contraindications are discussed. This case underlines the importance of awareness of neuropsychiatric side-effects with mefloquine use and of taking a careful psychiatric history before prescribing mefloquine.