In systemic lupus erythematosus (SLE) patients, the role of inflammatory mediators is relevant to the pathogenesis of accelerated atherosclerosis. CD40 ligand is increased on circulating lymphocytes, correlates with double-stranded DNA, and has an important role in predicting risk of cardiovascular disease. Vascular endothelial growth factor (VEGF) is a tightly regulated angiogenic cytokine in the kidney, and plasma levels have been associated with disease activity. It has been correlated with lupus nephritis, associated with higher mean carotid intima media thickness, and can be a novel cardiovascular risk factor in premature coronary atherosclerosis. VEGF has been demonstrated in cultured human aortic endothelial cells in the presence of simvastatin and in kidney biopsies in lupus nephritis. SLE patients have been shown to manifest disturbances in gene expression involved in lipid transport and atheroma promotion. This paper provides evidence of the immune system in accelerated atherosclerosis in SLE, the role of selected proinflammatory cytokines, and therapeutic approaches.