Monolayers of human peripheral blood monocytes in the absence of exogenous proteins ingest a variety of natural particulate activators of the human alternative complement pathway. Sheep erythrocytes, which do not ordinarily activate the human alternative complement pathway or initiate a direct monocyte phagocytic response, can be modified to exhibit both functions by the deletion or alteration of membrane sialic acid residues. Enzymatic removal of the sialic acid residues with sialidase or their conversion to heptulosonic acid derivatives by limited oxidation with NaIO4 and reduction with BH4- have equivalent dose-response effects on the capacity of the altered sheep erythrocytes to initiate the phagocytic response by human monocytes or to activate the alternative pathway in human serum. The deposition of C3b on native sheep erythrocytes had little effect on their ingestion by human monocytes, whereas the fixation of C3b on desialated sheep erythrocytes had a synergistic effect on the percentage of monocytes ingesting such a particle. The monocyte receptor essential for ingestion of desialated sheep erythrocytes or desialated sheep erythrocytes bearing C3b was inactivated by concentrations of trypsin that also prevented the monocytes from ingesting natural activators of the human alternative complement pathway, but did not alter the receptors for C3b or the Fc portion of IgG. The capacity of the nonimmune host to respond to desialated particles by initiating the monocyte ingestive process and by activating the alternative complement pathway to provide the synergy afforded by C3b deposition on that particle represents a primitive biochemical basis for differentiation of nonself from self.