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Phospholipase C-γ1 (PLC-γ1) activation has been reported to enhance cell survival during the cellular response to oxidative stress. We studied the role of protein kinase C (PKC) pathways in mediating PLC-γ1 survival signalling in oxidative stress by using mouse embryonic fibroblasts genetically deficient in PLC-γ1 (Plcg1−/−) and its wild type (Plcg1+/+). PLC-γ1 was activated by H2O2 treatment in a dose- and time-dependent manner. Activation of PKC was also markedly increased in both cell lines treated with H2O2 (1–5mM), but with low doses (50–200μM), PKC activation was considerably decreased in Plcg1−/− cells. After treatment with H2O2, PKC-dependent phosphorylation of Bcl-2 and cell viability of Plcg1−/− cells decreased dramatically and caspase-3-like activity increased significantly compared with that of the wild-type cells. Furthermore, pretreatment of Plcg1+/+ cells with PKC-specific inhibitor decreased levels of PKC-dependent Bcl-2 phosphorylation, enhanced caspase-3 activity and their sensitivity to H2O2. On the contrary, treatment of Plcg1−/− cells with PKC-specific activator increased the Bcl-2 phosphorylation, decreased caspase-3 activity and improved their survival. These results suggest that PLC-γ1 mediates survival signalling in oxidative-stress response by PKC-dependent phosphorylation of Bcl-2 and inhibition of caspase-3.