Mefloquine hydrochloride is now one of the major antimalarial drugs used both in prophylactic and therapeutic regimens. Large-scale studies have shown that it is efficacious and relatively well tolerated. However, some severe side effects, particularly neuropsychiatric reactions, have been described. We describe two young men with no previous medical history who experienced severe psychiatric reactions during prophylactic and curative mefloquine therapy. In both cases, full recovery was rapid after cessation of the therapy. There is no explanation for these reactions. Serum levels of mefloquine were within the normal range. The absence of contraindications and minor side effects during an initial course of mefloquine should be confirmed before another course is prescribed.