The ability of muramyl dipeptide (MDP), its adjuvant inactive stereoisomer, MDP(D-D), and the non-pyrogenic, adjuvant active analogue, MDP-butyl ester (MDP-BE), to induce in vitro proliferation and/or polyclonal activation (PA) of peripheral blood mononuclear cells (PBMNC) from normal volunteers, was studied. MDP, as well as its two analogues, were incapable of inducing 3H-thymidine uptake or immunoglobulin synthesis in PBMNC cultures from the majority of the individuals tested. However, these muramyl peptides were capable of regulating the in vitro proliferative responses of some individuals to concanavalin A and to soluble antigens of Candida albicans. At the same time, enhancement of the pokeweed mitogen-induced IgA and IgM but not IgG PA was observed with MDP, its adjuvant active analogue MDP-BE, but not with the adjuvant inactive stereoisomer MDP(D-D). Results are discussed with relation to a possible genetic restriction of the responsiveness to MDP.