A role of interferon-γ is suggested in early development of atherosclerosis. However, the role of interferon-γ in progression and destabilization of advanced atherosclerotic plaques remains unknown. Thus, the aim of this study was to determine whether postnatal inhibition of interferon-γ signaling could inhibit progression of atherosclerotic plaques and stabilize the lipid- and macrophage-rich advanced plaques. Atherosclerotic plaques were induced in ApoE-knockout (KO) mice by feeding high-fat diet from 8 weeks old (w). Interferon-γ function was postnatally inhibited by repeated gene transfers of a soluble mutant of interferon-γ receptors (sIFNγR), an interferon-γ inhibitory protein, into the thigh muscle every 2 weeks. When sIFNγR treatment was started at 12 w (atherosclerotic stage), sIFNγR not only prevented plaque progression but also stabilized advanced plaques at 16 w: sIFNγR decreased accumulations of the lipid and macrophages and increased fibrotic area with more smooth muscle cells. Moreover, sIFNγR downregulated expressions of proinflammatory cytokines, chemokines, adhesion molecules, and matrix metalloproteinases but upregulated procollagen type I. sIFNγR did not affect serum cholesterol levels. In conclusion, postnatal blocking of interferon-γ function by sIFNγR treatment would be a new strategy to inhibit plaque progression and to stabilize advanced plaques through the antiinflammatory effects.