Abstract Purpose The Scandinavian Starch for Severe Sepsis/Septic Shock (6S) trial showed increased mortality in patients resuscitated with hydroxyethyl starch 130/0.42 (HES) vs Ringer acetate. Different effects of the fluids on the endothelium may have contributed to the observed outcome. We aimed to investigate associations between HES vs Ringer and changes in plasma biomarkers reflecting endothelial damage and coagulation impairment. Materials and methods Six biomarkers, including soluble thrombomodulin (sTM) and plasminogen activator inhibitor 1 (PAI-1), were assessed in a subgroup of 208 patients from the 6S trial. We analyzed differences in plasma concentration in the 2 intervention groups using linear or logistic regression models. Results The increase in plasma sTM was lower in the HES group (− 1.8 ng/mL; 95% confidence interval, − 2.9 to − 0.7; P = .002). The change was not statistically significant associated with mortality whereas increase in plasminogen activator inhibitor 1 was (odds ratio for 1-unit increase, 1.04; 95% confidence interval, 1.01-1.08; P = .01). Conclusions Resuscitation with HES vs Ringer decreased early endothelial damage. Although this finding should be interpreted with caution, it indicates that the increased mortality observed with HES in the 6S trial may not be explained by endothelial damage and it emphasizes the challenge of using surrogate markers as outcome.