Objectives: When used as a cardioplegic solution, Custodiol® HTK solution is typically administered in a single-dose, allowing the operation to be performed continuously. This is an advantage over alternative cardioplegic solutions that may have to be re-administered every 20-30 minutes. Although Custodiol is widely used as a cardioplegic solution in Europe, its use for myocardial protection remains an off-label indication in the United States. Thus, the aim of this study is to compare the efficacy of Custodiol to standard 4:1 blood cardioplegia in adult cardiac cases. METHODS: This study was a single-center retrospective review of prospectively collected data. Adult cardiac cases performed between November 2011 and August 2013 using Custodiol® were compared to cases using standard Plegisol® 4:1 blood cardioplegia. Twenty-six primary intra-operative and post-operative endpoints were compared including 30-day mortality, 30-day hospital readmission, prolonged mechanical ventilation time, and renal failure. RESULTS: Of the 229 cases identified, 63 cases used Custodiol and 166 used 4:1 blood cardioplegia. Demographics were similar in both groups with a mean patient age of 65.27±15.07 years for Custodiol and 66.72±12.85 years for 4:1 blood cardioplegia. The average cardiopulmonary bypass time for Custodiol and 4:1 blood cardioplegia was 124.76±61.45 and 137.93±54.05 minutes respectively. The Custodiol group had a greater incidence of prolonged ventilation (>24 hours), 20.6% versus 15.1% respectively, and this approached statistical significance with a p value of 0.052. Intra-operative blood usage was significantly higher in the Custodiol group compared to the blood cardioplegia group, with 44.4% of patients receiving fresh frozen plasma during the operation compared to only 25.3% in the blood cardioplegia group (p=0.005). The results revealed no statistically significant difference in 30-day mortality, 30-day hospital readmission, renal failure, and stroke. CONCLUSION: Despite the distinct advantage of long-term ischemic tolerance, Custodiol use was associated with an increased requirement for fresh frozen plasma during the perioperative period when compared to blood cardioplegia.