Background: To determine the relevance of drug interactions with co-medication for effectiveness and tolerability of antimalarial chemoprophylaxis. Method: A database (MALPRO2) on travelers on their flight home from Africa to Europe between July 1988 and December 1991 was reanalyzed. It contains data on prophylaxis with mefloquine (n = 48,264), with chloroquine (6,752), with chloroquine plus proguanil (19,727), and with no prophylaxis (3,871). The comparison of rates of malaria incidence and adverse events (AEs) between users and nonusers of co-medication was expressed by relative risk (RR). Results: Fifty-three percent of travelers (63% of females, 43% of males) used co-medication in all prophylaxis groups, with an average of 1.35 additional drugs per person and about two AEs reported per person. With the exception of antidiarrheals plus mefloquine, malaria incidence with co-medication was lower (RR = 0.8) than without co-medication. In all regimens, the proportion of travelers reporting AEs was about 1.5-fold with co-medication (p<.01); that reporting severe AEs was twice as high as compared to with no co-medication. Mefloquine AE rates for various classes of co-medication were similar to that of chloroquine, with highest AE and severity rates with neuropsychiatric drugs (excluding antiepileptics, RR = 1.9 and 2.9), and lowest rates with cardiovasculars (RR = 1.1 and 1.0). Various co-medications were used with different frequencies in males and females, and the latter reported more AEs. Conclusion: These data suggest that co-medications commonly used by travelers have no significant clinical impact on safety and effectiveness of prophylaxis with mefloquine or chloroquine. Increased frequency and severity of AEs when using co-medication rather is explained by underlying illness.