In a volunteer with infection induced by injection of the mefloquine-sensitive, multidrug-resistant Vietnam Smith isolate of P. falciparum, parasitemia recurred following treatment with the candidate antimalarial drug enpiroline. Parasitemia also recurred after subsequent treatment with mefloquine and again after retreatment with the same drug. All recurrences were at the RI level. Parasite drug sensitivities determined by a semi-automated isotope microdilution method after the second and third recurrences revealed a progressive decrease in sensitivity to all arylaminoalcohols tested (halofantrine, enpiroline, and mefloquine). Decreased sensitivity persisted after 30 days of isolate culture. The parallel changes in parasite sensitivity to the synthetic arylaminoalcohols argue for development of drugs which are chemically dissimilar.