The Na,K-ATPase is a heterodimeric ion pump consisting of various combinations of a catalytic α-subunit (α1, α2, α3, or α4, encoded by ) and a β-subunit (β1, β2, or β3, encoded by ). We have previously shown that knock-out (ko) mice exhibit rapid photoreceptor cell degeneration, whereas knock-in (ki) mice, which express the β1-subunit instead of the β2-subunit under regulatory elements of the gene, exhibit slowly progressive retinal dystrophy. Here, we performed a detailed analysis of the retinal phenotype of the ki mouse. We found that the number of cone photoreceptor cells in the mutant retinas was significantly reduced by postnatal day 28. The retinas of 4-month-old mice were almost devoid of cones. The early onset and rapid loss of cones was followed by a slowly progressive degeneration of rods. Other retinal cell types were unaffected. Nonradioactive hybridization and immunohistochemistry revealed that wild-type photoreceptors expressed β3 and high levels of β2, while ki photoreceptor cells expressed β3 and low levels of transgenic β1. Additionally, levels of retinoschisin, a secreted retina-specific protein that interacts directly with the β2-subunit, were greatly reduced in mutant retinas. The results demonstrate that the β1-subunit can functionally compensate, at least in part, for the absence of the β2-subunit. The results also show that cones are more susceptible to Na,K-ATPase dysfunction than rods. Taken together, the present study identifies the ki mutant as a novel animal model of an early-onset and rapidly progressive cone-rod dystrophy.