Objective: To determine if loss of protein kinase Cγ (PKCγ) results in increased structural damage to the retina by hyperbaric oxygen (HBO), a treatment used for several ocular disorders. Methods: Six-week-old mice were exposed in vivo to 100% HBO 3 times a week for 8 weeks. Eyes were dissected, fixed, embedded in Epon, sectioned, stained with toluidine blue O, and examined by light microscopy. Results: The thicknesses of the inner nuclear and ganglion cell layers were increased. Destruction of the outer plexiform layer was observed in the retinas of the PKCγ - knockout mice relative to control mice. Exposure to HBO caused significant degradation of the retina in knockout mice compared with control mice. Damage to the outer segments of the photoreceptor layer and ganglion cell layer was apparent in central retinas of HBO-treated knockout mice. Conclusions: Protein kinase Cγ-knockout mice had increased retinal sensitivity to HBO. Results demonstrate that PKCγ protects retinas from HBO damage. Clinical Relevance: Care should be taken in treating patients with HBO, particularly if they have a genetic disease, such as spinocerebellar ataxia type 14, a condition in which the PKCγ is mutated and nonfunctional.