Activation of resting human B lymphocytes either by cross-linking their membranal IgM or by phorbol esters has been previously demonstrated to modulate the type II receptor for Fc gamma domains (Fc gamma RII): shortly after stimulation a decrease in IgG binding capacity and an enhancement of Fc gamma RII expression were observed. These were followed by the release of Fc gamma RII fragments from the cell membrane. Since protein phosphorylation is well-established signal transduction element, we examined whether Fc gamma RII may be a target of such activation induced phosphorylation. Resting (high density) and activated (low density) human tonsil B lymphocytes were stimulated either by cross-linking their surface IgM (sIgM) or by the phorbol ester TPA. This treatment induced specific phosphorylation of a 36 kd membrane protein. This polypeptide was shown to specifically bind to IgG-coated Sepharose beads or to monoclonal Fc gamma RII-specific antibody-coated Affi-Gel 10 beads; thus, it most probably corresponds to the Fc gamma RII of these cells. In addition, phosphorylation of a 20 kd protein with similar binding characteristics was also observed in several experiments. Both serine and tyrosine were the amino acids that underwent phosphorylation in the 36 kd Fc gamma RII. The extent of Fc gamma RII phosphorylation correlated with the increase in receptor expression as monitored by specific mAb binding and, at the same time, with the decrease in the capacity to bind IgG-sensitized erythrocytes. These results suggest that stimulation-induced phosphorylation of Fc gamma RII on B cells is an early signal transduction element involved in controlling B cell response.