PURPOSE. To show that hypoxia is necessary to prevent opaci-fication of the lens. Protein kinase C (PKC)-ε serves a role that is distinct from PKC-γ when both PKC isoforms are expressed in the lens. PKCε serves a very important role in hypoxic conditions, helping to prevent opacification of the lens. METHODS. Digital image analysis, confocal microscopy, dye transfer assay, coimmunoprecipitation, Western blot analysis, and enzyme activity assays were used, respectively, to study opacification of the lens, intercellular communications, cellular localization of connexin-43 (Cx43), and the interactions between PKCε, PKCγ, and Cx43 in the lens epithelial cells. RESULTS. Hypoxic conditions (1%-5% of oxygen) were very important in maintaining clarity of the lenses of wild-type (WT) mice. Normoxic conditions induced opacification of the WT lens. Lenses from the PKCε-knockout mice underwent rapid opacification, even in hypoxic conditions. Hypoxia did not induce apoptosis in the lens epithelial cells, judging by the absence of active caspase-3, and it did not change intercellular communication and did not affect the number and localization of junctional Cx43 plaques in the lens epithelial cell culture. Hypoxia activated PKCε, whereas phorbol ester (TPA), oxidation (H2O2), and insulin-like growth factor-1 (IGF-1) activated PKCγ and decreased the activity of PKCε. Hypoxia did not induce the phosphorylation of the Cx43. CONCLUSIONS. Hypoxia-induced activation of PKCε is very important in surviving hypoxia and maintaining the clarity of the lens. However, PKCγ is utilized in the control of Cx43 gap junctions.