Research evidence available in any and all languages was evaluated on the efficacy and tolerability of mefloquine chemoprophylaxis against malaria. 37 potentially eligible trials of mefloquine chemoprophylaxis were identified; 10 met the inclusion criteria of being trials conducted using nonimmune adult travelers and nontraveling volunteers where it was attempted to conduct a randomized comparison of mefloquine against placebo or against alternative standard prophylaxis. The 10 trials comprised 2750 nonimmune adult participants randomized to mefloquine or a control. One placebo-controlled trial directly examined malaria incidence and showed mefloquine to be highly effective in preventing malaria in an area of drug resistance. However, 4 placebo-controlled trials showed mefloquine to be poorly tolerated, with the number of withdrawals consistently higher in mefloquine treatment arms than in placebo arms. 5 field trials compared mefloquine with other chemoprophylaxis. Mefloquine was no worse tolerated than the other types of chemoprophylaxis, but there was a possible trend toward more withdrawals in mefloquine arms. The high withdrawal rates observed in the trials, presumably due to drug side effects, may limit mefloquine's effectiveness for routine prophylaxis among travellers. Mefloquine may, however, be useful in specific situations where there is a high risk of contracting chloroquine-resistant malaria and access to effective medical care is limited.