Ag-mediated B cell stimulation relies on phospholipase Cγ2 (PLCγ2) for Ca(2+) mobilization. Enzymatic activity of PLCγ2 is triggered upon Src homology 2 domain-mediated binding to the tyrosine-phosphorylated adaptor SLP65. However, SLP65 phosphorylation outlasts the elevation of cytosolic Ca(2+) concentration suggesting additional levels of PLCγ2 regulation. We show in this article that the functionality of the PLCγ2/SLP65 complex is controlled by the weakly characterized C2 domain of PLCγ2. Usually C2 domains bind membrane lipids, but that of PLCγ2 docks in a Ca(2+)-regulated manner to a distinct phosphotyrosine of SLP65. Hence, early Ca(2+) fluxing provides feed-forward signal amplification by promoting anchoring of the PLCγ2 C2 domain to phospho-SLP65. As the cellular Ca(2+) resources become exhausted, the concomitant decline of Ca(2+) dampens the C2-phosphotyrosine interaction so that PLCγ2 activation terminates despite sustained SLP65 phosphorylation.