Systemic sclerosis (scleroderma, SSc) is an autoimmune, connective tissue disorder that is characterized by impaired vascular function, increased oxidative stress, inflammation of internal organs, and impaired angiogenesis. Tight skin mice (Tsk−/+) have a defect in fibrillin-1, resulting in replication of many of the myocardial and vascular features seen in humans with SSc. D-4F is an apolipoprotein A-I (apoA-I) mimetic that improves vascular function in diverse diseases such as hypercholesterolemia, influenza, and sickle cell disease. Tsk−/+mice were treated with either phosphate-buffered saline (PBS) or D-4F (1 mg·kg−1·day−1for 6–8 wk). Acetylcholine and flow-induced vasodilation were examined in facialis arteries. Proinflammatory HDL (p-HDL) in murine and human plasma samples was determined by the cell-free assay. Angiostatin levels in murine and human plasma samples were determined by Western blot analysis. Hearts were examined for changes in angiostatin and autoantibodies against oxidized phosphotidylcholine (ox-PC). Angiogenic potential in thin sections of murine hearts was assessed by an in vitro vascular endothelial growth factor (VEGF)-induced endothelial cell (EC) tube formation assay. D-4F improved endothelium-, endothelial nitric oxide synthase-dependent, and flow-mediated vasodilation in Tsk−/+mice. Tsk−/+mice had higher plasma p-HDL and angiostatin levels than C57BL/6 mice, as did SSc patients compared with healthy control subjects. Tsk−/+mice also had higher triglycerides than C57BL/6 mice. D-4F reduced p-HDL, angiostatin, and triglycerides in the plasma of Tsk−/+mice. Tsk−/+hearts contained notably higher levels of angiostatin and autoantibodies against ox-PC than those of control hearts. D-4F ablated angiostatin in Tsk−/+hearts and reduced autoantibodies against ox-PC by >50% when compared with hearts from untreated Tsk−/+mice. Angiogenic potential in Tsk−/+hearts was increased only when the Tsk−/+mice were treated with D-4F (1 mg·kg−1·day−1, 6–8 wk), and cultured sections of hearts from the D-4F-treated Tsk−/+micewere incubated with D-4F (10 μg/ml, 5–7 days). Failure to treat the thin sections of hearts and Tsk−/+mice with D-4F resulted in loss of VEGF-induced EC tube formation. D-4F improves vascular function, decreases myocardial inflammation, and restores angiogenic potential in the hearts of Tsk−/+mice. As SSc patients have increased plasma p-HDL and angiostatin levels similar to the Tsk−/+mice, D-4F may be effective at treating vascular complications in patients with SSc.