Highly abundant short-chain alcohol dehydrogenases (RDHs) in the retina were assumed to be involved in the recycling of 11-cis-retinal chromophore in the visual cycle. Mutations in human RDH genes are associated with Fundus albipunctatus, a mild form of night blindness (RDH5) and an autosomal recessive, childhood-onset severe retinal dystrophy (RDH12). Rdh12 knockout mice were found to be susceptible to light-induced photoreceptor apoptosis, whereas Rdh5 and Rdh8 knockout mice displayed only delayed dark adaptation. However, each knockout mouse eventually regenerated normal levels of visual pigments, suggesting that RDHs compensate for each other in the visual cycle. Here, we established RDH double knockout (Rdh8^−/−Rdh12^−/−) and triple knockout (Rdh5^−/−Rdh8^−/−Rdh12^−/−) mice generated on various genetic backgrounds including a rod α-transducin knockout to test cone function. RDH activity was severely reduced in Rdh8^−/−Rdh12^−/− retina extracts, whereas Rdh8^−/− RDH activity was intermediate and Rdh12^−/− RDH activity was reduced only slightly. Surprisingly, all multiple knockout mice produced sufficient amounts of the chromophore to regenerate rhodopsin and cone pigments in vivo. Three-month-old Rdh8^−/−Rdh12^−/− mice characteristically displayed a slowly progressing rod–cone dystrophy accompanied by accumulation of N-retinylidene-N-retinylethanolamine (A2E), a toxic substance known to contribute to retinal degeneration. A2E accumulation and retinal degeneration were prevented by application of retinylamine, a potent retinoid cycle inhibitor. The results suggest that RDH8 and RDH12 are dispensable in support of the visual cycle but appear to be key components in clearance of free all-trans-retinal, thereby preventing A2E accumulation and photoreceptor cell death.