Opiates are major analgesics and addictive drugs described also as immunomodulators. Here, we investigated the contribution of kappa-opioid receptor (KOR) activity in immunity in vivo by studying immune responses in KOR knockout mice. These animals displayed a modest reduction in thymus cellularity and CD4(+) cell ratio, parallel to a slight increase in immature CD4(+)CD8(+) lymphocytes. In spleen, KOR null animals showed augmented cell number with no change in cell distribution. T and B lymphocyte proliferative capabilities in vitro, Natural Killer activity and steady-state Ig levels were unchanged in KOR-/- mice. We immunized the mice with the antigen keyhole limpet hemocyanin (KLH). Compared to wild-type (WT) mice, KOR-/- animals produced significant higher levels of antigen-specific total Ig, IgM, IgG1 and IgG2a antibodies. This enhancement of humoral activity was not observed in mu-opioid receptor and delta-opioid receptor knockout animals. These results show that endogenous activation of kappa-opioid receptors may exert a tonic inhibition of antibody (Ab) response.