Purpose: It has not been fully understood how smoking habit promotes atherosclerosis. We have reported that LDL modified by cigarette smoke (CS) extracts accelerates foam cell transformation of macrophage. In this study, we examined the effect of HDL preincubated with CS extracts (CS-HDL) upon cholesterol efflux from the macrophagederived foam cells. We also tested the inhibitory effect of various radical scavengers on CS modification of HDL. Methods: HDL was separated from the plasma of healthy human subjects. CS-HDL was prepared by incubating HDL with CS-extracts entrapped in PBS. Mouse peritoneal macrophages were converted into foam cells by preincubation with 50 μg/ml acetyl LDL for 6 hrs. The cells were then incubated either with 50 μg/ml native HDL or CS-HDL for 30 hrs and cholesterol efflux from the cells was measured. Results: Incubation with CS-extracts caused marked decrease in the effect of HDL on cholesterol efflux from foam cells: the removal of cholesterol from the cells by CS-HDL was 68% of that by native HDL (p < 0.05). Superoxide dismutase suppressed CS-modification of HDL by 52% (p < 0.05), whereas glutathione had no such effect. Conclusion: Superoxide anion in CS-extracts may promote atherogenesis by causing modification of HDL, which could reduce efflux of cholesterol from the macrophage-derived foam cells.