The hypolipidemic properties of ethyl 6-chlorochroman-2-carboxylate (II), 6-phenylchroman-2-carboxylate (III) and 6-cyclohexylchroman-2-carboxylate (IV) were compared to clofibrate (I) in sucrose-fed fasted male Sprague-Dawley rats. All compounds were administered at doses of 0.2 and 0.4 mmol/kg, orally, twice daily for 7 consecutive days. In this model, II was a more effective hypocholesterolemic drug than clofibrate, whereas III and IV were inactive. Chlorochroman II, like clofibrate, decreased serum alpha-lipoprotein cholesterol and pre-beta-lipoprotein triglyceride concentrations and concomitantly increased serum beta-lipoprotein triglyceride concentrations. In clofibrate-treated rats, serum free cholesterol concentrations increased concurrent with a reduction in serum lecithin: cholesterol acyltransferase activity, but no such correlation was observed for II. Only II lowered liver cholesterol levels and increased liver triglyceride levels. No consistent inhibition of liver microsomal 3-hydroxy-3-methylglutaryl-CoA reductase activity was observed with these analogs. The observed changes in triglyceride and cholesterol concentrations among serum lipoproteins were of a greater magnitude after chlorochroman II and clofibrate administration to sucrose-fed rats than in our previous studies using chow-fed fasted rats. These data suggest that chloro-substitution at the 6-position of the phenylchroman ring is important for hypolipidemic activity of these cyclic clofibrate analogs.