The effect of Poly D, L-lactide-co-glycolic acid (PLGA) encapsulated ODN 1668 nanospheres (NS) on innate and adaptive immune response in common carp, Cyprinus carpio against Aeromonas hydrophila is reported. PLGAencapsulated ODN biodegradable NS did not have a significant impact on particle size as expected of the particles was clearly positive for non-coated and coated PLGA/ODN NS. The myeloperoxidase (MPO) activity and serum haemolysin titre significantly increased in fish injected with ODN 1668 and PLGA-encapsulated ODN 1668 groups on week 4 whereas the respiratory burst (RB) activity significantly increased when administered with ODN 1668 and PLGA-encapsulated ODN 1668 (PLGA-ODN 1668) from weeks 1 to 4. The haemoagglutinating titre was significantly enhanced in PLGA-encapsulated ODN 1668 group on week 2 while in ODN 1668 and PLGA-encapsulated ODN 1668 groups the increase manifested on week 4. The bacterial agglutination titre significantly increased in ODN 1668 and PLGA-encapsulated ODN 1668 groups on weeks 2 and 4. The cumulative mortality in ODN 1668 and PLGAencapsulated ODN 1668 groups were 10% each whereas it was 15% in PLGA group. This study indicates that single administration of PLGA-encapsulated ODN 1668 nanospheres elicits better immune response than PLGA or ODN 1668 alone in C. carpio against A. hydrophila.