Abstract Although CD4 antigen is expressed on monocytes (MØ), its functional role is uncharacterized. In this study, isolated human MØ were separated into CD4+ and CD4- MØ subsets and assessed for presentation of tetanus toxoid. The CD4- MØ subset had decreased antigen presenting cell (APC) capacity as well as increased PGE2 production when compared to the CD4+ MØ subset. Addition of a cyclo-oxygenase inhibitor (Indo-methacin) did not restore the CD4- MØ subset's APC capacity to that of the similarly treated CD4+ MØ subset, eliminating differential PGE2 production as the primary cause of differential APC capacity. Production of monokines such as IL-1 and plasminogen activator, which affect APC capacity, was similar in the CD4 MØ subsets. However, tumor necrosis factor (TNF) production (IFNγ plus MDP-induced) of the CD4+ MØ subset was slightly greater than that of the CD4- MØ. CD4- MØ's lower APC capacity is not totally explained by their differential IL-1, TNF, or PGE2 production.