Impaired Fcγ receptor-mediated phagocytosis has been reported in monocytes from HLA-DR2- and -DR3-positive disease-free individuals compared to normals without these B cell alloantigens. We have noted, however, a decrease in the ingestion of concanavalin A (Con A)-treated rabbit erythrocytes (E-Con A) in the same immunogenetically defined groups (DR2 vs Other: 2.94 ± 0.84 erythrocytes/monocyte vs 4.16 ± 1.37, p < 0.003; DR3 vs Other: 3.35 ± 1.51 vs 4.16 ± 1.37, p < 0.04). These data raised the possibility that carbohydrate-lectin interactions might trigger ingestion mediated by the Fcγ receptor. To test this hypothesis, we performed receptor modulation and monosaccharide blocking experiments. Modulation of the Fcγ receptor off the apical cell surface of monocytes by adherence to solid-phase IgG aggregates specifically reduced internalization of E-Con A and IgG-sensitized erythrocytes (EA) to 9.1% and 10.6% of control, respectively (p < 0.001). Internalization of wheat germ agglutinin-treated erythrocytes, tannic acid-treated erythrocytes, and zymosan was not inhibited. In reciprocal modulation experiments using solidphase Con A, no effects on phagocytosis of any particle was observed. α-Methyl mannoside, O.1 M in PBS, did not inhibit the internalization of EA but blocked ingestion of E-Con A by 97% (p < 0.001). Other monosaccharides had little or no effect on the ingestion of any of the phagocytic probes. These data demonstrate that a mechanism integrally involving the Fcγ receptor mediates the ingestion of E-Con A by human monocytes. This Fc receptor has an oligosaccharide(s) with an exposed mannose which may be functionally significant. Whereas the mannose moiety does not play a crucial role in the interaction of the Fcγ receptor with the Fc portion of IgG, engagement of the receptor via mannose can initiate internalization. Our findings raise the possibility that nonimmune functions may utilize classical immune system receptors through carbohydrate interactions. Furthermore, the ability of the Fcγ receptor to trigger internalization is defective in HLA-DR2 and -DR3 normals, whether the receptor is ligated at its clasical ligand-binding site or by way of its carbohydrate moieties.