Large increases in mortality related to premature atherosclerosis with coronary artery disease and stroke have been reported in patients with systemic lupus erythematosus (SLE), antiphospholipid syndrome (APLS), or rheumatoid arthritis (RA). Studies found relative risks of 5 for myocardial infarction, 6 to 10 for stroke in SLE patients, and 3.6 for cardiovascular deaths in RA patients. The main risk factors for atherosclerosis included not only the classic factors identified in epidemiological studies such as the Framingham study (advanced age, high cholesterol levels, hypertension, diabetes mellitus, and obesity), but also prolonged glucocorticoid therapy, long duration of SLE, postmenopausal status, and heart failure. SLE per se is an independent risk factor. The current pathogenic hypothesis for atherosclerosis involves an inflammatory response (erythrocyte sedimentation rate, C-reactive protein, and fibrin), autoantibodies, immune complexes (containing antibodies to phospholipids, to oxidized LDLs, and to endothelial cells), cytokine-producing activated T cells, and bacterial or viral infections responsible for an immune response against heat shock proteins (endogenous HSP60 and its equivalent, bacterial HSP65). Early risk factor intervention and effective control of inflammation should be incorporated into the management of connective tissue disease with the goal of protecting patients against atherosclerosis.