We describe a high incidence of Plasmodium vivax malaria among travelers returning from Ethiopia, who all took the recommended prophylaxis. Three groups of 7-11 nonimmune travelers received mefloquine (250 mg weekly), beginning 1-2 weeks prior to departure and continuing for 4 weeks after their return. A fourth group mistakenly took inadequate prophylaxis and is presented for comparison. Vivax malaria occurred at a rate of up to 50% in the first three groups; nearly all patients became ill 3 months after exposure. In the fourth group, primary attacks of both falciparum and vivax malaria occurred within 1 month of return, at an incidence of 50%. The use of mefloquine prevented Plasmodium falciparum infection, but a very high rate of relapses of P. vivax infection occurred. The complexity of prophylaxis for malaria in an area with a high rate of both P. falciparum and P. vivax infections and the urgent need for effective causal prophylaxis are discussed.