Receptors for the Fc fragment of IgG (Fc gamma R) have a well-documented role in the generation of oxidative burst. It is tempting to speculate that the type of interaction with Fc gamma R could be a mechanism of regulation of this process. Here we report on a comparative study of the induction of oxidative burst in human monocytes activated by means of different types of interaction with Fc gamma R. We studied non-primed monocytes obtained by centrifugal elutriation from healthy donors. These cells were submitted to Fc gamma R interactions following two distinct models: one, using particulate material (IgG-SRBC leading to phagocytosis or rosetting), and another using soluble reagents followed by cross-linking of the receptors (monoclonal antibodies against Fc gamma RI and Fc gamma RII and natural ligands, namely several isotypes of murine and human IgG). Phagocytosis and oxidative burst were studied simultaneously in the monocytes, following the methodology described recently. Human non-primed monocytes were able to generate a very obvious oxidative burst response after activation of Fc gamma R by particulate material. The same response was observed when Fc gamma RII was blocked by monoclonal antibodies. Ingestion was not necessary for activation of the oxidative burst, since the model of rosetting induced a level of burst generation similar to the one obtained in the phagocytic process. Cross-linking of Fc gamma RI by soluble reagents induced production of reactive oxidative intermediates (ROI) only when the ligand-binding site of the receptor was involved. These data lead to the conclusion that Fc gamma R interaction with soluble or particulate material induces oxidative burst in non-primed human monocytes only when the binding site of natural ligands is involved. The type of interaction also determines the efficiency of the generation of ROI. This fact could represent a regulatory mechanism.