Streptococcal toxic shock syndrome (STSS) is characterized by diffuse vascular leak resulting from widespread endothelial activation. Angiopoietin-1 and -2 (Ang-1 and Ang-2), which are important regulators of endothelial quiescence and activation, respectively, are dysregulated in certain diseases that are associated with endothelial dysfunction, but they have not been previously investigated in STSS. Plasma Ang-1 and Ang-2 concentrations were measured in 37 patients with invasive streptococcal infection with and without concurrent STSS. Greater angiopoietin dysregulation (decreased Ang-1 and increased Ang-2) occurred in STSS than in invasive infection without shock; dysregulation decreased with convalescence. These results suggest that systemic Ang-1 and Ang-2 dysregulation is associated with disease severity in invasive streptococcal infection and that plasma levels of Ang-1 and Ang-2 may serve as clinically informative biomarkers in STSS.