It has previously been demonstrated that soya protein, which contains isoflavones and low methionine-glycine and lysine-arginine ratios, has a hypocholesterolaemic effect. In the present study, the hypocholesterolaemic effects of an isoflavone-enriched casein diet (HDI) and a single-cell protein-based diet (SCP) devoid of isoflavones but with low methionine-glycine and lysine-arginine ratios were investigated in obese Zucker rats after 6 weeks of feeding. The control diet contained casein, which has high ratios of methionine-glycine and lysine-arginine. HDI and SCP feeding reduced the concentrations of total cholesterol and cholesteryl esters in plasma and liver, and changed the fatty acid composition of the hepatic cholesteryl esters. Faecal cholesterol and bile acid levels were markedly higher in SCP-fed rats than in controls, whereas HDI feeding had only minor effects. However, both HDI and SCP feeding increased the hepatic gene expression of cholesterol 7alpha hydroxylase. In contrast, the hepatic acyl-CoA synthetase and acyl-CoA:cholesterol acyltransferase activities and the gene expression of the LDL receptor were increased by HDI, but not by SCP feeding. The present results suggested that the cholesterol-lowering effect of SCP was related to the enterohepatic circulation, whereas HDI seemed to lower the plasma cholesterol via the circulation. Plasma homocysteine level was reduced in rats fed HDI and SCP compared to rats fed casein. In summary, diets enriched in isoflavones or containing proteins with low methionine-glycine and lysine-arginine ratios lowered the plasma cholesterol and homocysteine levels, changing the plasma profile from atherogenic to cardioprotective.