The combination effects of chloroquine with Cepharanthin^® or minocycline hydrochloride were evaluated against a blood-induced infection with chloroquine-resistant P. berghei NK 65 in ICR mice. The infected mice in an untreated control group showed a progressively increasing parasitemia leading to mouse death. A two-day dosage of 20 mg base/kg of chloroquine alone produced little effect against P. berghei NK 65 infection, and all mice died from day 13 to 15 with an increasing parasitemia. A four-day dosage of 4 mg/kg of Cepharanthin^® alone produced no antimalarial activity, and all mice died by day 10. A four-day dosage of 50 mg/kg of minocycline hydrochloride alone produced a slight effect, but all mice died by day 18. Furthermore, mice given chloroquine in combination with Cepharanthin^® died from day 14 to 15. Mice given Cepharanthin^® plus minocycline hydrochloride also died from day 15 to 17. On the other hand, infected mice treated with chloroquine plus minocycline hydrochloride survived during the experiment. All mice treated with chloroquine alone, minocycline hydrochloride alone, chloroquine plus Cepharanthin^® or Cepharanthin^® plus minocycline hydrochloride showed low parasitemia levels during drug administration and a few subsequent days, but then malaria parasites re-increased in the bloodstream of the treated mice until death. On the other hand, malaria parasites in the mice given chloroquine plus minocycline hydrochloride decreased on day 6 and then could not be detected by microscopic examination during the observation period. This finding strongly suggests that the combination effects of chloroquine and minocycline hydrochloride are worthy of evaluation in human malaria. The results also clearly demonstrate the necessity and importance of in vivo experiments in estimating the activities of drugs.