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The study evaluates in vivoantimalarial activity of arteether and garlic pearl oil combination in Plasmodium berghei-infected mouse model of malaria. 72h (Day 3) post infection, at 2–4% parasitemia, mice were treated with single dose intramuscular injection of α-β arteether, at 750μg, in combination with three 100μL oral doses of garlic pearl oil on Day 3, Day 4 and Day 5. Following the treatment, 100% protection and survival of mice were observed. Inhibition of parasitemia in combination treated animals and protection during recrudescence interval of α-β arteether monotherapy was observed in Giemsa-stained blood smears. In addition, a striking increase in anti-parasite antibody IgG contributing protective immunity during the recrudescence phase was observed. These results correlate with western blot analysis, where sera from the recrudescence stage and later period of arteether and garlic oil combination treated animals found to interact with several parasite specific proteins as compared to controls. The present approach shows that arteether and garlic pearl oil combination provides complete protection in P. berghei-infected mice. Thus, for the first time, garlic pearl oil appears to be an ideal antimalarial candidate in artemisinin combination therapy.