A diet supplemented with cholesterol and coconut oil is atherogenic in dogs. The purpose of the present study was to examine the effects of this diet on red cells in pure-bred beagles and greyhounds. Within 3 days after the initiation of this diet red cell cholesterol/phospholipid increased and membrane fluidity decreased, with maximum changes attained by 12 weeks. Serum lipoprotein cholesterol/phospholipid also increased, and serum from cholesterol-fed dogs transferred cholesterol to normal red cells. Significant abnormalities of liver function developed in all cholesterol-fed dogs. Hematocrit declined beginning at 6 weeks, with a parallel increase in osmotic fragility. Reticulocytes were elevated in beagles but normal in greyhounds. Red cell morphology resembled acanthocytes or spur cells. All red cell parameters returned to normal within 4 weeks after stopping the diet. These studies demonstrate that a cholestrol-enriched, atherogenic diet causes profound and reversible changes in the lipid composition, membrane fluidity, and morphology of red cells in dogs.