Treatment of normal or puromycin aminonucleoside-nephrotic rats, kept on a balanced Purina chow diet, with beta, beta'-tetramethyl-substituted hexadecanedioic acid (MEDICA 16) (Bar-Tana, J., G. Rose-Kahn, and M. Srebnik. 1985. J. Biol. Chem. 260: 8404-8410) resulted in an acute reversible inhibition of liver lipogenesis and cholesterogenesis with a concomitant hypolipidemic effect which was sustained as long as the drug was administered. The hypolipidemic effect in normal and nephrotic rats consisted of 70-80% and 40-60% reduction in plasma VLDL-triacylglycerols and cholesterol, respectively, with a respective increase in the HDL-cholesterol/(VLDL + LDL)-cholesterol ratio. The observed hypolipidemic effect was accompanied by a 10-fold decrease in VLDL-apoC-III content with a concomitant enrichment of the VLDL fraction by VLDL remnants having an increased apoB-100/apoB-48 ratio. The pharmacological reduction of VLDL by MEDICA 16 may offer a treatment mode of choice for selected hyperlipidemic states.