Experiments were performed to determine the turnover processes of plasma cholesterol in genetically hypercholesterolemic rats (RICO). Specific activity of plasma cholesterol was monitored during 4 months following an intravenous injection of tritiated cholesterol. The results were subjected to two-pool model analysis. Cholesterol production in the RICO rat was significantly higher (28.9 +/- 1.7 mg/d) than in the SW control (18.5 +/- 0.7, P < .01). The study also revealed a 30% decrease in the rate constant for cholesterol movement from the plasma toward the majority of organs in the RICO rat versus the SW control. Very-low-density lipoprotein (VLDL), low-density lipoprotein (LDL), and high-density lipoprotein (HDL) turnover were investigated following injection of labeled lipoproteins (on cholesteryl ester or apolipoproteins). Results from these experiments showed that the higher HDL cholesterol concentration in the RICO rat as compared with the control is due to the greater production rate of esterified cholesterol in these lipoproteins (1.3 +/- 0.05 mg/h v 0.8 +/- 0.03 in the control, P < .001). The fractional catabolic rate (FCR) or production rate for VLDL were not significantly different between the two groups (3.4 +/- 0.01 and 3.6 +/- 0.01 h-1 and 2.6 +/- 0.4 and 3.3 +/- 0.1 mg/h, respectively). However, radioactivity of VLDL recovered in LDL at death was considerably higher in RICO rats (14% +/- 1% v 6% +/- 1%, P < .01). The greater concentration of LDL cholesterol in RICO rats is due to a higher LDL production (0.40 +/- 0.05 v 0.19 +/- 0.03 mg/h, P < .01) together with a lower catabolism (FCR, 5.5 +/- 0.6 v 7.9 +/- 0.8%/h, P < .05). Cross-injection experiments showed that this lower catabolism of LDL is partly due to the nature of the lipoprotein particle. Taken together, these data are consistent with the hypothesis of a reduced uptake of apolipoprotein (apo)E-containing lipoproteins (VLDL and LDL), which results in a higher LDL cholesterol concentration in RICO rats.