In the present study, we investigated the effects of apolipoprotein A-I (apoA-I) on matrix metalloproteinase-2 (MMP-2) expression in vivo and in vitro. First, we detected the effects of apoA-I on aorta MMP-2, peroxisome proliferator-activated receptor α/γ (PPAR α/γ), cyclooxygenase-2 (COX-2), and nuclear factor kappa B (NF-κB) expressions in atherosclerotic rabbit models using immunohistochemical methods. The results showed that the expressions of MMP-2, COX-2, and NF-κB were decreased in aortas of atherosclerotic rabbits treated with apoA-I, while PPAR α/γ expression was increased. Then, we chose the important inflammation cells, macrophages to testify those effects in vitro. Macrophages were divided into six groups and treated with different concentrations of apoA-I, the mRNA expressions of MMP-2, PPAR α/γ, and COX-2 were then determined using reverse-transcription polymerase chain reaction, and protein expression of PPAR γ, NF-κB were detected by western blot analysis. The levels of MMP-2 and PPAR α in cultured supernatants were determined using enzyme-linked immunosorbent assays. Interestingly, the in vitro results were similar to the results of the in vivo study. After incubation with apoA-I for 24 h, the expressions of MMP-2, COX-2, and NF-κB were decreased, while PPAR α/γ expression was increased. In consideration of their particular roles in the process of making plaque stable in vivo and in vitro, we speculate that the inhibitory effect of apoA-I on MMP-2 expression may have a close relationship with the effects of apoA-I on PPAR α/γ, COX-2, and NF-κB expressions. Although further research is needed to clarify the underlying mechanisms of these effects, our findings provide a novel insight into the anti-atherosclerotic plaque rupture effects of apoA-I.