Activators of the alternative C pathway were ingested by human monocytes in a synthetic medium devoid of serum or proteins of the alternative C pathway. The rank order of the percentage of human monocytes ingesting rabbit, mouse C57B, and mouse CBA erythrocytes was the same as that observed for lysis of these erythrocytes by the alternative C pathway in C2-deficient human serum diluted in GVB-Mg-EGTA. Sheep and guinea pig erythrocytes, which were not ingested by human monocytes, were not lysed by the alternative C pathway. Although the capacity of human monocytes to ingest rabbit erythrocytes was consistent for a particular donor, there was a bimodal distribution among donors in terms of the percentage of monocytes involved. Zymosan ingestion, on the other hand, was observed with a high proportion of monocytes from all donors. The capacity of human monocytes to ingest zymosan particles and rabbit erythrocytes was largely diminished when the monocytes were pretreated with quantities of affinity-purified trypsin, which had little or no effect on their ability to phagocytose EA or even to bind E(IgM)C43b intermediates. Latex particles that did not activate the alternative pathway of C were ingested by human monocytes after treatment with a concentration of trypsin 10 times that required to reduce substantially ingestion of zymosan. The trypsin-sensitive mechanism of monocytes involved in the ingestion of zymosan and rabbit erythrocytes was regenerated over 48 hr during in vitro culture and is a result compatible with the restoration of function of a membrane protein. The capacity of human monocytes to ingest particulate activators of the alternative C pathway in the absence of surface-associated opsonizing proteins such as IgG or C3b by a trypsin-sensitive step represents a monocyte recognition mechanism specific for activating surfaces of the alternative C pathway.