Previous epidemiological studies have suggested that the LpA-I subfraction of HDL is more protective than the LpA-I:A-II subfraction against the development of cardiovascular disease. A possible basis for a specific anti-atherogenic function of LpA-I emerged from studies of cholesterol efflux from cultured mouse adipocytes. LpA-I efficiently removed excess cholesterol from the mouse adipocytes, while LpA-I:A-II was ineffective. On the other hand, LpA-I:A-II was able to stimulate cholesterol efflux from a number of other cell types including rodent macrophages. Because of previously reported differences in HDL stimulation of cholesterol clearance from macrophages of different origins, we determined whether LpA-I:A-II could induce cholesterol efflux from cultured human monocyte-macrophages. Our findings showed that LpA-I:A-II and HDL3 effectively stimulated cholesterol efflux from human monocyte-macrophages enriched with cholesterol by incubation with AcLDL. LpA-I:A-II also decreased by one-half the amount of cholesterol accumulated when macrophages were incubated with AcLDL and LpA-I:A-II together. Thus, it would appear that the differential anti-atherogenic effects of LpA-I:A-II and LpA-I do not derive from their effects on macrophage cholesterol efflux. Possibly these HDL subfractions differentially affect other biologic processes that modulate the development of cardiovascular disease.