Some or most of the turnover of lipoprotein lipase (LPL) occurs by dissociation from vascular endothelial sites in extrahepatic tissues and further degradation in the liver. Heparin greatly enhances this dissociation and delays but does not abolish uptake in the liver, raising the possibility that heparin could lead to accelerated catabolism of functional LPL. To investigate this, we determined time curves for heparin (anti-factor Xa activity) and for LPL and hepatic lipase after injection in rats of two doses of conventional unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH). The high dose (250 U/kg) of both heparins resulted in similar initial levels of LPL activity in plasma, but at 30 minutes the activity with LMWH had declined by more than 80%, whereas with UFH it remained essentially unchanged during this time. In contrast, time curves for heparin activity in blood were similar for the two heparins. The low dose (50 U/kg) led to lower initial levels of LPL activity with LMWH in spite of slower elimination of heparin activity from the blood. These results agree with previous studies that indicate that LMWH has a similar ability as UFH to release LPL, but a lesser ability to delay its removal by the liver. Only slight differences were noted in the time curves for hepatic lipase with the two heparins. To assess the possible depletion of the Upases, we administered a second large dose of conventional heparin. One hour after the first injection, the second injection resulted in lower plasma LPL activities in all four groups. This depletion of releasable LPL was more pronounced with high-dose LMWH (49% of that in saline-treated controls versus about 60% in the other groups). The LPL activity released by the second injection remained significantly depressed with low-dose LMWH and the high dose of either heparin at 4 hours, but had returned to normal after 24 hours. By contrast, no depletion of hepatic lipase activity could be shown at any time. The results showed that release of LPL into the circulating blood is followed by a period during which time the stores of functional LPL are depleted. This occurs with both UFH and LMWH; the difference between the two heparins lies more in the kinetics of the LPL removal process than in its ultimate result.