This study aimed to investigate the relationship between type I interferon (IFN-I) and plaque stability in pristane-treated apolipoprotein E-knockout (ApoE-/-) mice. Antinuclear antibody (ANA) and extractable nuclear antigen antibody (ENA) levels were measured by immunofluorescence and enzyme-linked immunospot assay. Atherosclerotic plaques were detected by Sirius red/fast green staining. Cell apoptosis was detected by terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick-end labeling. Gene expression was determined by real-time PCR analyses. We found that pristane-treated ApoE-/- mice developed a lupus-like syndrome characterized by an increased production of serum ANA and ENA. Pristane treatment decreased the collagen content and increased the number of apoptotic cells in plaques. Moreover, IFN-induced ISG15, IFIT1-1, and IFIT1-2 gene expression was increased in peripheral blood cells and aortic plaques. An IFN-α-stimulated macrophage supernatant inhibited collagen type I, alpha 1 gene expression in vascular smooth muscle cells. We concluded that the vulnerability of plaques was associated with the activation of IFN-I in pristane-treated ApoE-/- mice. Thus, we speculated that the higher prevalence of cardiovascular events in patients with systemic lupus erythematosus could be due to plaque instability.