ATP-binding cassette transporter A1 (ABCA1) plays a crucial role in apoA-Ⅰ binding activity and promotes cellular cholesterol efflux. In order to investigate the effect of interaction between apoA-Ⅰ and ABCA1 on atherosclerosis, and to discover the mechanism of interaction between apoA-Ⅰ and ABCA1, THP-1 cells were induced to become the macrophages by the phorbol. Then THP-1 macrophages were induced to the foam cells by ox-LDL. Treatment of THP-1 macrophage derived foam cells with apoA-Ⅰ, forskolin (FRK, an adenyl cyclase activator), and SQ-22536 (an adenyl cyclase inhibitor) for long periods of time (24 h). In addition, THP-1 macrophage derived foam cells were treated with increasing amounts of FRK (0, 10, 20, 40 and 80 μmol/L) and treated with FRK for increasing time(0, 6, 12 and 24 h). Cholesterol efflux, ABCA1 mRNA and protein level were determined by FJ-2107P type liquid scintillator, reverse transcriptase-polymerase chain reaction and Western blotting, respectively. Cellular lipid accumulation was determined by Oil Red O staining and high performance liquid chromatography analysis. The cholesterol efflux of control group, apoA-Ⅰ group, FRK group, apoA-Ⅰ+ FRK group and apoA-Ⅰ+SQ-22536 group was (8.64 ± 0.83)%, (9.8 ± 0.93)%, (10.15 ± 0.98)%, (11.72 ± 1.1)%, and (6.77 ± 0.7)%, respectively. ApoA-Ⅰ resulted in a 26.7% increase in protein expression of ABCA1, and a 14.0% increase in cholesterol efflux from THP-1 macrophage derived foam cells (P < 0.05). The similar results have been observed in foam cells treated with FRK. ApoA-Ⅰ, in combination with FRK, contributed to a much larger increase in protein expression of ABCA1 (80%, P < 0.05) and cholesterol efflux (36%, P < 0.05) from THP-1 macrophage derived foam cells. In converse, treatment THP-1 macrophage derived foam cells with apoA-Ⅰ and SQ-22536 markedly down-regulated protein expression of ABCA1 (26.7%, P < 0.05) and decreased cholesterol efflux (22.1%, P < 0.05). However, apoA-Ⅰ, FRK and SQ-22536 alone or combination did not influence mRNA expression of ABCA1. These findings suggest that apoA-Ⅰ may stabilize ABCA1 protein, and then increase cellular cholesterol efflux through PKA signaling.