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Objective: To compare the efficacy of methylene blue with combination therapy with hydroxocobalamin in patients experiencing vasoplegic syndrome after cardiac surgery., Design: Retrospective cohort study., Setting: Tertiary medical center., Participants: Patients who received methylene blue with or without hydroxocobalamin for refractory vasoplegic syndrome rescue therapy., Measurements and Main Results: The primary outcome was 0.the ability to maintain mean arterial pressure (MAP) >60 mmHg beyond 1hour after study drug administration. Other pertinent outcomes included MAP at hours 6, 12, and 24 post-administration; both raw and proportional changes of vasopressor doses from baseline at hours 1, 6, 12, and 24 post-administration; and change in pulmonary artery catheter hemodynamics. Overall, 28 doses were administered in 14 patients in the monotherapy group and 17 doses (10 methylene blue, 7 hydroxocobalamin) were administered in 6 patients in the combination therapy group. There were no differences in ability to maintain MAP at 1hour, with 71% of the monotherapy and 82% of combination therapy patients meeting MAP goals (p = 0.49). Pairwise comparisons demonstrated vasopressor reductions at 6, 12, and 24hours in both groups, but only significant reductions at 1hour were observed in the combination therapy group (-0.06 µg/kg/min; p = 0.003) but not in the monotherapy group (-0.015 µg/kg/min; p = 0.14)., Conclusion: This is the first study to compare methylene blue monotherapy with combination therapy, which suggests there may be an advantage to combination therapy. Further characterization of ideal dosing, timing, and agent selection should be investigated on a larger scale format., (Copyright © 2018 Elsevier Inc. All rights reserved.)