Purpose: To analyze in vivo the function of chicken acidic leucine-rich epidermal growth factor-like domain containing brain protein/Neuroglycan C (gene symbol: Cspg5) during retinal degeneration in the Rpe65(-/-) mouse model of Leber congenital amaurosis. Methods: We resorted to mice with targeted deletions in the Cspg5 and retinal pigment epithelium protein of 65 kDa (Rpe65) genes (Cspg5(-/-)/Rpe65(-/-)). Cone degeneration was assessed with cone-specific peanut agglutinin staining. Transcriptional expression of rhodopsin (Rho), S-opsin (Opn1sw), M-opsin (Opn1mw), rod transducin a subunit (Gnat1), and cone transducin a subunit (Gnat2) genes was assessed with quantitative PCR from 2 weeks to 12 months. The retinal pigment epithelium (RPE) was analyzed at P14 with immunodetection of the retinol-binding protein membrane receptor Stra6. Results: No differences in the progression of retinal degeneration were observed between the Rpe65(-/-) and Cspg5(-/-)/Rpe65(-/-) mice. No retinal phenotype was detected in the late postnatal and adult Cspg5(-/-) mice, when compared to the wild-type mice. Conclusions: Despite the previously reported upregulation of Cspg5 during retinal degeneration in Rpe65(-/-) mice, no protective effect or any involvement of Cspg5 in disease progression was identified.