Synthetic oligodeoxynucleotides (ODN) containing unmethylated CpG motifs act as immune adjuvants, improving the immune response elicited by coadministered vaccines. Combining CpG ODN with anthrax vaccine adsorbed (AVA), the licensed human vaccine, can increase the speed, magnitude and avidity of the resultant anti-anthrax response in mice, rhesus macaques and humans. Adsorbing the CpG ODN onto cationic poly(actide-coglycolides) microparticles further boosts immunity to coadministered AVA. The antibody response induced by CpG ODN plus AVA confers protection against systemic anthrax challenge in multiple animal models. These findings suggest that CpG ODN, alone or in combination with other adjuvants and delivery strategies, may support the development of prophylactic and therapeutic vaccines against biothreat pathogens.