Twenty-seven menopausal women were given the synthetic progestin levonorgestrel for two weeks. The mean plasma high-density lipoprotein (HDL) cholesterol concentration decreased from 1.32 mmol/l to 1.01 mmol/l (p less than 0.001) during treatment. This was due to the selective reduction in plasma HDL2 cholesterol from 0.73 mmol/l to 0.44 mmol/l, whereas the plasma HDL3 cholesterol was not changed. The mean hepatic lipase (HL) activity of postheparin plasma increased from 20.6 to 35.3 mumol.h-1.ml-1 (p less than 0.001) while the lipoprotein lipase (LPL) activity was not changed. A significant inverse correlation existed between the HDL2 cholesterol concentration and HL activity both before (r=-0.49, p less than 0.01) and after (r=-0.39, p less than 0.05) treatment, and a significant correlation was observed between the changes in these two variables (r=0.39, p less than 0.05). These results are compatible with the hypothesis that HL participates in the regulation of plasma HDL2 levels and they suggest that progestin treatment reduces plasma HDL2 cholesterol concentration by increasing the hepatic lipase activity. It is not known whether this type of HDL2 reduction is accompanied by increased atherogenesis but as long as the issue is unresolved some caution is needed in the long-term use of levonorgestrel, particularly in women who simultaneously are given some other drug depressing plasma HDL2 concentration.