This study explores the expression and localization of phosphoinositide 3-kinase enhancer (PIKE) in the retina, unveiling its potential role in retinal degenerative diseases. Phosphatidylinositol 3-kinase (PI3K) activation is pivotal for photoreceptor functions, linked to retinal degenerative disorders. PIKE, an enhancer of PI3K/Akt activities, remains unexplored in retinal physiology. Through immunohistochemistry, immunoblots, and real-time PCR, we examined PIKE in rod-dominant and cone-dominant retinas of wild-type mice and models of diabetes and retinal degeneration. PIKE was present in photoreceptor inner segments, outer nuclear, and ganglion cell layers. Both short and long forms were detected in rod- and cone-dominant retinas. Protein overlay assays revealed PIKE binding to specific layers although exact partners remain unidentified. These findings underscore PIKE's significance in retinal degenerative diseases and justify the need for further exploration of therapeutic implications.