The safety of mefloquine has not been well described in military populations. This study used standard military databases for mefloquine prescriptions and hospitalizations to investigate mefloquine safety among US service members from 2002 through 2004. Mefloquine-prescribed and deployed personnel (N = 8,858) were compared with two reference groups. The reference groups comprised US service members who were not prescribed mefloquine and resided in Europe or Japan (N = 156,203) or had been otherwise deployed (N = 232,381). In comparison with active-duty US service members residing in Europe or Japan, mefloquine-prescribed service members were at statistically significant decreased hazard for any-cause hospitalization, as well as diseases of the respiratory and digestive systems, musculoskeletal system and connective tissue diseases, injuries and poisonings, ill-defined conditions, and mood disorders. These results suggest there is no association between mefloquine prescriptions and severe health effects, as measured by hospitalizations, across a wide range of outcomes.