ATP-binding Cassette Transporter A1 (ABCA1) plays a critical role in the reverse cholesterol transport (RCT). Previous studies showed that paraoxon, the active metabolite of organophosphorus insecticide, increased cholesterol retention in macrophages. However, its underlying mechanisms remain to be elucidated. The effect of paraoxon on ABCA1 expression and ABCA1-dependent cholesterol efflux was investigated, and then the role of cyclic adenosine monophospate (cAMP) signaling pathway in the regulation of ABCA1 expression and ABCA1-mediated cholesterol efflux was examined by paraoxon in RAW 264.7 macrophage-derived foam cells. Results showed that paraoxon significantly down regulated ABCA1 expression and reduced ABCA1-dependent cholesterol efflux and increased the levels of the total, free and esterified cholesterols in a time- and dose-dependent manner. Paraoxon also markedly reduced cAMP level and decreased adenylate cyclase (AC) activity and increased cAMP-specific phosphodiesterase (PDE) activity. Furthermore, cAMP analogs dibutyryl cyclic adenosine monophosphate (dBcAMP) markedly compensated the down-regulation of ABCA1 expression and partly compensated the reduction of ABCA1-mediated cholesterol efflux induced by paraoxon. Also, both adenylate cyclase agonist forskolin and phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX) markedly compensated the suppression effect on cAMP level induced by paraoxon. In conclusion, the results mentioned above suggest that paraoxon down regulates ABCA1 expression and decreases ABCA1-mediated cholesterol efflux through cyclic AMP signaling pathway in RAW 264.7 macrophage-derived foam cells.