Activation of B lymphocytes by engagement of their immunoglobulin M antigen receptors results in phosphorylation of a number of proteins on tyrosine residues. One such protein is p95vav, the product of the vav proto-oncogene. Tyrosine phosphorylation of p95vav occurred within seconds of immunoglobulin M cross-linking and was independent of other events induced during stimulation of B cells, such as protein kinase C activation, guanosine triphosphate-binding protein signaling, and calcium mobilization. Moreover, engagement of antigen receptors induced the rapid (approximately 5 seconds) and transient (approximately 60 seconds) association of p95vav with a 70-kilodalton tyrosine-phosphorylated protein, Vap-1, an interaction mediated by the Src homology 2 domain of p95vav. These results suggest that the vav proto-oncogene participates in the signaling processes that mediate the antigen-induced activation of B lymphocytes.