Activation of the innate immune system by different homotopes may direct the subsequent specific immune response, and as a consequence may have significant implications on vaccination. In this study, effects of i.v. administered lipopolysaccharide (LPS), and lipoteichoic acid (LTA), respectively, and s.c. administered Keyhole Limpet Hemocyanin (KLH) on total and isotype-specific (IgM and IgG) primary and secondary antibody responses of chickens to human serum albumin (HuSA) were determined. Similarly, effects of pre-treatment of the birds with the homotopes on primary antibody responses to rabbit gamma globulin (RGG) were measured. In addition, antigen-specific (HuSA and RGG) and mitogenic (concanavalin A, Con A) responses of peripheral blood leucocytes in vitro were also measured. Our findings confirm earlier observations that both LTA as well as LPS have immunomodulatory features in chickens, albeit in an opposite direction. LTA enhanced primary and to a minor degree secondary antigen-specific antibody titers, but LPS was found to suppress these responses. In RGG-primed birds, LPS enhanced a non-antigen-specific recall response to HuSA. In addition, KLH acted in an immunomodulatory role too, enhancing primary and secondary antibody responses, but suppressing non-specific cellular immunity in a non-antigen-specific fashion. Possible mechanisms underlying our observations, and the role of LTA, LPS, and KLH in polarization of the specific antibody response in chickens are discussed.