A hypercholesterolemic diet fed to rats revealed significant interstrain differences in plasma cholesterol levels. Hyperresponding and hyporesponding strains could be distinguished from normoresponding strains within 3 weeks. The increase in plasma cholesterol level was more than 300 mg/100 ml in the hyperresponding strains BN/Cpb, SD/Cpb and WE/Z and less than 50 mg/100 ml in the hyporesponding strains S3/Cpb and SHR/Cpb. These differences were primarily genetically determined: the calculated coefficient of genetic determination (g2) of the response was 0.84. The response is not correlated with variation in plasma esterase or alkaline phosphatase isozyme patterns.