This study evaluated the relationship between plasma vitamin A and cholesterol in 48 patients with hypercholesterolemia studied before and after treatment with a cholesterol-lowering diet, with or without lipid-lowering medication. Plasma vitamin A levels were higher in hypercholesterolemic subjects than in healthy controls (2.58 +/- 0.15 vs. 1.82 +/- 0.14 mmol/L, p = 0.025) despite similar values for retinol binding protein (RBP). Successful cholesterol lowering, defined as greater than 25% reduction in low density lipoprotein cholesterol, was achieved in 16 patients. In this subset, plasma vitamin A declined from 3.00 +/- 0.32 (pretreatment) to 2.34 +/- 0.15 mmol/L (post treatment; p = 0.018). A nonsignificant increase in RBP was observed, resulting in a significant decrease in the molar ratio of vitamin A to RBP (1.05 +/- 0.06 vs. 0.80 +/- 0.05, p = 0.013). These data suggest an interaction between vitamin A and cholesterol that is independent of the transport mechanisms for vitamin A in association with chylomicrons (post absorptive) and with RBP. Further examinations of the form or forms of vitamin A (retinol, retinyl ester), its distribution within the plasma lipoproteins, and the mechanisms of origin and removal are warranted to explain these findings.