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Background: Psychiatric events during travel abroad account for a large percentage of medical repatriations arranged by insurance companies. Several risk factors have been proposed for such events, one of these being use of mefloquine. We investigated the risk of psychiatric events during use of mefloquine., Method: We performed a nationwide case control study using medical records from 4 large alarm centers in the Netherlands. Cases were patients contacting the alarm centers because of psychiatric events, according to International Code Primary Care code P (all psychiatric symptoms) or International Classification of Diseases, Ninth Edition, codes 290-319 (all psychiatric syndromes). To every case we matched up to 6 controls by alarm center, calendar time, and continent of travel. All controls had contacted the alarm centers because of nonpsychiatric medical reasons. Shortly after the anticipated day of return, cases and controls received a questionnaire regarding travel characteristics, gender, age, marital status, education, weight, height, general health, history of psychiatric diseases, use of medicines, smoking status, alcohol intake, coffee intake, and use of malaria prophylaxis. Dates of travel for the source population were between September 1, 1997, and June 1, 2000., Results: The study population consisted of 111 cases and 453 controls. The risk of psychiatric events during the use of mefloquine was 3.5 (95% CI = 1.4 to 8.7). In females, the risk was strongly increased, with an odds ratio of 47.1 (95% CI = 3.8 to 578.6). Stratification for history of psychiatric diseases showed that the risk of psychiatric events during use of mefloquine in cases without a history of psychiatric diseases was 3.8 (95% CI = 1.4 to 10.1), whereas the risk in cases with a history of psychiatric diseases was 8.0 (95% CI = 1.8 to 35.8)., Conclusion: The use of mefloquine is associated with an increased risk of psychiatric events in females and in patients with a history of psychiatric diseases.