Technical Abstract: Poultry coccidiosis is the major parasitic disease of poultry and until now no recombinant vaccine has been developed; rather the poultry industry relies on prophylactic medication and live vaccines. Short oligodeoxynucleotides (ODNs) containing unmethylated CpG motifs (CpG ODNs) have been shown to be effective immunoprotective agents and vaccine adjuvants in mammalian systems. Their use in poultry to protect against intracellular parasites has not been reported to date. The present work investigated the effects of CpG ODN treatment on host susceptibility to Eimeria infection in two chicken strains with different genetic background, SC and TK. The data show that CpG ODN enhanced the birds' resistance to coccidiosis in a normally susceptible chicken strain (TK), as shown by reduced oocyst shedding and improved weight gain. CpG treatment had a differential effect on body weight gains and serum antibody responses depending on the chicken strain and ODN dose, delivery route, and backbone. This study shows for the first time that CpG ODNs could be used as immunoprotective agents in Eimeria-infected chickens to boost resistance to the pathogen and improve performance. Future research is needed to optimize their use alone and as vaccine adjuvants leading to practical application in the poultry industry and reducing the economic impact of coccidiosis and other poultry diseases.