T4 replacement at 150 micrograms/day in a group of six hypothyroid subjects led to the development of a euthyroid state and produced a fall in the cholesterol content of plasma and low and high density lipoproteins (LDL and HDL). The effect of T4 on apolipoprotein-B (apoB) metabolism was followed using radioiodinated very low density lipoprotein1 (VLDL1; 60-400 Svedberg units) and VLDL2 (20-60 Svedberg units). The pretreatment plasma concentration of VLDL1 apoB and its rates of synthesis and catabolism were similar to those in normal subjects. VLDL2 apoB was synthesized at a supranormal rate in hypothyroid subjects, and this led to a doubling of its circulating mass. Treatment did not significantly alter the kinetics of apoB in either VLDL1 or VLDL2. The concentration of intermediate density lipoprotein (IDL) apoB in untreated hypothyroids was 170% of normal and fell during T4 treatment due to stimulation of conversion of LDL (from 0.46 +/- 0.14 to 0.91 +/- 0.30 pools/day; mean +/- SD; P < 0.01). Direct IDL apoB clearance was not altered by treatment, whereas the fractional catabolic rate of LDL increased 76% (from 0.17 +/- 0.06 to 0.27 +/- 0.07 pools/day), leading to a 36% decrement in LDL mass. The stimulation of IDL to LDL conversion during therapy was probably due to a 3-fold increase in hepatic lipase activity (P < 0.02). This change together with the known effects of T4 on LDL receptors largely explained the lipoprotein abnormality in hypothyroidism and the effects of replacement therapy.