Heparin activates lipoprotein lipase (LPL) and hepatic lipase (HL), enhances plasma lipolytic activity and elevates plasma levels of free fatty acids (FFA). The metabolic consequences of this effect are controversial. In this study the plasma lipolytic effect of unfractionated heparin (mean molecular weight, MW, 12,000-15,000) was compared with that of a low molecular weight heparin (LMWH) fragment (Kabi 2165, Fragmin, mean MW 4000-6000). The comparisons which were carried out in vivo and in vitro in both man and rat were based on the antifactor Xa activity of the two heparins. After i.v. injection of LMWH the release of LPL activity was only half as great as with heparin and the increase in plasma FFA was significantly lower. The immediate release of HL activity was the same for both heparins, the release of LPL activity was dose-dependent and the elimination followed first-order kinetics. After subcutaneous administration, LMWH was absorbed faster than heparin but still had a negligible effect on plasma lipolysis. With simultaneous i.v. infusions of fat emulsion, glucose and heparin or LMWH to healthy subjects no different effects on fat oxidation were seen in spite of pathological increases in plasma FFA with heparin. Also, heat production from isolated adipocytes was not affected by heparin or LMWH. Enzyme release was greater with LMWH in tissue preparations of fat, skeletal muscle and heart muscle in vitro, however. In isolated fat cells no difference in the release of LPL was seen between the two heparins. In conclusion, the plasma lipolytic effect of LMWH is significantly weaker than that of heparin. The complex-binding between heparin and LPL is dependent on the degree of sulphation or ionic strength of the heparin. In the LPL-release from tissue preparations, the molecular size of the heparin is of greater significance, however. Regardless of the degree of plasma lipolytic activity of the two heparin preparations, the fat oxidation rate is not affected. Considering the toxic effects of high levels of plasma FFA, LMWH, with its weak lipolytic potential would appear to be preferable to heparin as an anticoagulant agent.