Based on the results of recentin vitrostudies, tau has been proposed to be involved in regulating signal transduction through the phospholipase C-γ (PLC-γ) signaling pathway. The present study provides support for the physiological relevance of this hypothesis by demonstrating the existence of a tau-PLC-γ complexin situin a human neuroblastoma cell line. Both PLC-γ and PLC-δ, but not PLC-β, co-purified with microtubule-associated proteins. PLC-γ, but neither PLC-δ nor PLC-β, co-immunoprecipitated with tau, and the PLC co-precipitating with tau was enzymatically active. Additionally, both tau and MAP-2 co-precipitated with PLC-γ. These studies indicate that tau associates, either directly or indirectly, with PLC-γin situ, suggesting that tau may be appropriately localized to participate in the regulation of signal transduction through the PLC-γ pathwayin vivo.