Background: A carbon monoxide-releasing molecule (tricarbonyldichlororuthenium (II) dimer; CORM-2) enhances coagulation and attenuates vulnerability to fibrinolysis in normal and hemophiliac human plasma. We tested the hypothesis that plasma diluted with resuscitative fluids would demonstrate improved coagulation and decreased fibrinolytic vulnerability after exposure to CORM-2. Methods: Normal, platelet-poor plasma was diluted 0%, 20%, 30%, 40%, or 50% with 0.9% NaCl (NS) or low-molecular-weight hydroxyethyl starch (VOL) and, subsequently, exposed to 0 μmol/L or 100 μmol/L CORM-2 before activation with tissue factor (n = 4 per condition). Additional plasma samples diluted with NS or VOL (0% or 30%) were exposed to 0 μmol/L or 100 μmol/L CORM-2 and 0 U/mL or 100 U/mL tissue-type plasminogen activator to assess fibrinolytic vulnerability (n = 8 per condition). Thrombelastographic data were collected until either clot strength stabilized or clot lysis occurred, as appropriate. Results: CORM-2 exposure maintained normal to supranormal velocity of clot formation and strength in plasma diluted up to 40% with NS. In contrast, although CORM-2 exposure improved coagulation kinetics, dilution with VOL markedly degraded thrombus formation kinetics. Similarly, fibrinolytic vulnerability to tissue-type plasminogen activator was markedly improved by CORM-2 exposure in samples diluted with NS, whereas VOL-diluted thrombi were still abnormally weak and easily lysed compared with undiluted samples despite CORM-2 exposure. Conclusion: CORM-2 exposure attenuated the decrease in coagulation kinetics and enhancement of fibrinolytic vulnerability associated with hemodilution. Extensive preclinical investigation remains to be performed to determine the route of administration, safety, and efficacy of CORM-2 and other CORMs to treat trauma-associated bleeding. Copyright © 2011 by Lippincott Williams & Wilkins.