Administration of high-dose hydroxocobalamin, or vitamin B12, is an emerging, targeted rescue therapy for the treatment of refractory vasoplegic shock. This is an uncommon but potentially life-threatening complication following cardiac surgery and carries a poor prognosis, particularly when patients fail to respond to first-line therapy with catecholamine vasopressors. This study describes our experience in treating refractory vasodilatory shock following cardiac surgery with high-dose hydroxocobalamin. Administration of hydroxocobalamin in seven patients was associated with an improvement in mean arterial blood pressure or reduction in vasopressor requirements, which were both immediate and sustained throughout our observational period. No deaths or adverse effects attributable to hydroxocobalamin administration occurred in our cohort. Our observations show that high-dose hydroxocobalamin is a safe and effective rescue therapy in refractory vasoplegic shock post cardiopulmonary bypass (CPB).