G-CSF primed CD34 cells cultured for 2–3 weeks in IL-2 and stem cell factor generate CD56 high cells with phenotypic and morphologic features of NK cells, and a novel adherent CD56 low CD16− population expressing myeloid markers (CD33 and HLA-DR). We hypothesized that similar cells might also occur in peripheral blood. In 13/13 normal individuals, we found a circulating population of CD56 low, CD33+, FcγRI+, FcγRII+, HLA-DR+, CD11b high, CD14+ monocytes closely resembling the cultured CD56 low CD33+ cells. They may represent a normal counterpart of the CD56+ CD33+ hybrid myeloid/natural killer cell leukemia. Their mean frequency was 1.3±1%(standard deviation), range 0.16–3.5%, of total mononuclear cells. CD56 low CD33+ cells, primed with cytomegalovirus antigen, induced autologous T-lymphocyte proliferation comparably to CD56−, CD14+ peripheral blood monocytes (PBM). Conversely, CD56 low cells induced greater T-cell proliferation than CD56− PBM when lymphocyte responders were HLA mismatched. Unstimulated CD56 low CD33+ cells showed a low antiproliferative effect on K562, which was increased upon LPS stimulation. The pattern of cytokine production by CD56 low CD33+ cells and PBM largely overlapped; however, they produced detectable levels of IL-6 and IL-1β. These results define a minor monocyte population with distinct phenotypic and functional features.