OBJECTIVE: To determine whether anti-apolipoprotein A-1 (anti-Apo A-1) IgG are associated with major cardiovascular events in patients with rheumatoid arthritis (RA). METHODS: We determined anti-Apo A-1 IgG levels and the concentrations of cytokines, oxidized low-density lipoprotein (LDL), and matrix metalloproteinase 1 (MMP-1) MMP-2, MMP-3, and MMP-9 in sera from 133 patients with RA who did not have cardiovascular disease at baseline, all of whom were longitudinally followed up over a median period of 9 years. A major cardiovascular event was defined as a fatal or nonfatal stroke or acute coronary syndrome. The proinflammatory effects of anti-Apo A-1 IgG were assessed on human macrophages in vitro. RESULTS: During followup, the overall incidence of major cardiovascular events was 15% (20 of 133 patients). At baseline, anti-Apo A-1 IgG positivity was 17% and was associated with a higher incidence of major cardiovascular events (adjusted hazard ratio 4.2, 95% confidence interval 1.5-12.1). Patients who experienced a subsequent major cardiovascular event had higher circulating levels of anti-Apo A-1 IgG at baseline compared with those who did not have a major cardiovascular event. Receiver operating curve analysis showed that anti-Apo A-1 IgG was the strongest of all tested biomarkers for the prediction of a subsequent major cardiovascular event, with an area under the curve value of 0.73 (P = 0.0008). At the predefined and previously validated cutoff levels, the specificity and sensitivity of anti-Apo A-1 IgG to predict major cardiovascular events were 50% and 90%, respectively. Anti-Apo A-1 IgG positivity was associated with higher median circulating levels of interleukin-8 (IL-8), oxidized LDL, and MMP-9 and higher proMMP-9 activity as assessed by zymography. On human macrophages, anti-Apo A-1 IgG induced a significant dose-dependent increase in IL-8 and MMP-9 levels and proMMP-9 activity. CONCLUSION: Anti-Apo A-1 IgG is an independent predictor of major cardiovascular events in RA, possibly by affecting vulnerability to atherosclerotic plaque.