Polarized Caco-2 cells can synthesize two distinct density classes of lipoproteins, i.e. chylomicron/VLDL (d <1.006 g/ml) or IDL/LDL density (1.009 <d <1.068 g/ml). When saturated fatty acid in the incubation medium is replaced with unsaturated fatty acid, this results in an increase in the basolateral secretion of triglycerides from 18.6 +/- 3.6 nmol/filter (with 0.5 mmol/l 16:0) to 21.4 +/- 6.2, 27.5 +/- 4.8 and 28.9 +/- 5.3 nmol/filter when 10, 20 or 30% of 16:0 were substituted by 18:1. The secretion of IDL/LDL-sized lipoproteins diminished and chylomicron/VLDL secretion increased in proportion to the increase of unsaturated fatty acid in the medium. To gain insight into the relationship between these lipoprotein classes, we determined their secretion at several time intervals (0-4, 4-8 and 22-26 h) after incubation with a fatty acid mixture containing 16:0 and 18:1 in a 9:1 molar ratio (total fatty acid concentration was 0.5 mmol/l). Chylomicron/VLDL secretion was detectable immediately upon the start of the incubation and persisted during all intervals. In contrast, IDL/LDL density lipoproteins were first detectable in the 4-8 h time interval and their secretion was highest in the final phase of the incubation (22-26 h). We conclude that Caco-2 cells secrete two distinct density classes of lipoproteins that show no precursor-product relation.