Serum squalene, a non-steroid intermediate of cholesterol biosynthesis, originates mainly from endogenous cholesterol synthesis and partly from diet, especially in populations consuming a lot of olive oil rich in squalene. Its postabsorptive metabolism has not been studied in detail in humans. Its presence in chylomicrons and VLDL suggests that the removal of dietary squalene may reflect the metabolism of intestinal lipoproteins. Accordingly, we studied the postabsorptive metabolism of 1 g dietary squalene in 16 healthy subjects with apolipoprotein (apo) E 3/3 phenotype and in five type III hyperlipidemic apo E 2/2 homozygotes known to have a retarded chylomicron remnant removal, and compared the results with vitamin A fat load test. About 40% of the basal and 90% of the postabsorptive squalene was in lipoproteins < 1.019 g/ml. The peak concentrations of chylomicron squalene were at 6 h, and of triglyceride-rich nonchylo-fraction at 9-12 h in the controls. The peak values occurred later than those of vitamin A. At 24 h the levels still exceeded the basal ones. In type III dyslipoproteinemia, most of the basal and postabsorptive squalene was in lipoproteins of density less than 1.019 g/ml, the peak postabsorptive values occurred later than in the controls and the serum values remained above the control levels for up to 24 h. The squalene and vitamin A areas under the incremental response curves (AUC) were higher than in the control group. The AUCs of the two markers in chylomicron were correlated negatively and those in LDL+HDL were correlated positively with fasting HDL cholesterol levels, the respective correlations being opposite with fasting VLDL triglycerides. The postabsorptive profile of squalene levels resembled that of vitamin A in both groups, except that the squalene curves were shifted to a later time period. Thus, a delayed clearance of chylomicron remnants could be detected by analyzing serum squalene 6-24 h after the squalene-supplemented fat meal.