Quinacrine resistance has been induced in 3 Giardia duodenalis laboratory stocks and 4 lines resistant to other drugs. The quinacrine-resistant lines were maintained in normally lethal levels of 5 microM quinacrine and some lines are viable in 20 microM levels of the drug. Fluorescence studies indicated that quinacrine was taken up by sensitive cells but was actively excluded from resistant trophozoites. The nuclei were not a site of drug accumulation and no specific fluorescence in the trophozoite could be attributed to any structure. Blebs of concentrated drug appeared prior to disintegration of the membrane of drug-sensitive trophozoites exposed to drug overnight. Parasite lines already resistant to furazolidone adapted more readily to quinacrine exposure than drug-sensitive stocks. This multiple drug resistant phenotype was not as marked with metronidazole-resistant lines.