Fibronectin (FN) and serum amyloid P component (SAP) markedly enhance phagocytosis mediated by the C3b and C3bi receptors of cultured human monocytes but not of granulocytes. (The C3b and C3bi receptors of granulocytes can be activated by treatment of these phagocytes with PMA.) Activation of monocyte C3 receptors by FN is developmentally regulated: Freshly explanted monocytes respond to FN with a small increase in C3 receptor-mediated phagocytosis while monocytes matured in culture exhibit a much greater response. The mechanism of action of FN on C3 receptors of cultured monocytes is unique in two respects. First, while substrate-bound FN or SAP activate monocyte C3 receptors, soluble FN does not. Second, stimulation of the basal surface of monocyte plasma membranes by substrate-bound FN activates C3b and C3bi receptors on the apical surface of the plasma membrane, i.e., at sites remote from the segments of membrane in contact with the FN or SAP.