Objective : Prevention of gastrointestinal bleeding is imperative in perioperative management of open-heart surgery. Although both proton pump inhibitors (PPIs) and Warfarin are often prescribed to patients following cardiac surgery, the US FDA warns that PPIs increase the international normalized ratio (INR) when used concomitantly with Warfarin, by being metabolized by cytochrome P-450 (CYP) 2C19. We assessed whether this drug interaction depends on the genotype of CYP2C19 (Extensive Metabolizer, EM ; Intermediate Metabolizer, IM ; Poor Metabolizer, PM) or the type of PPI. Methods and Results : In this observational prospective study, the CYP2C9, CYP2C19, and VKORC1 genotypes of 78 patients were analyzed. After excluding cases with ^*1/^*3 of the CYP2C9 genotype and those with C/T of the VKORC1 genotype, 60 patients were assigned to Warfarin+Rabeprazole (RB group, 30 cases) or Warfarin+Lansoprazole (LP group, 30 cases). Warfarin was started with an initial dose of 3 mg, and INR values were measured on days 4, 8, 14, 28, and 56. There was no significant difference in median Warfarin dose between the LP group (2.5 mg/day) and RB group (3.0 mg/day), (p=0.88). The time in the therapeutic range (TTR) (Rosendaal) was significantly higher in the RB group (83.7%) than in the LP group (49.4%), and the time in the over range was significantly higher in the LP group (41.9%) than in the RB group (0.0%). In the LP group, TTR values were higher in CYP2C19 Extensive Metabolizers (EMs) than in Intermediate Metabolizers (IMs) and Poor Metabolizers (PMs), but there was no statistically significant difference between them. Conversely, in the RB group, there was no difference in the values of any CYP2C19 genotype. A multivariate analysis showed that high age and low TTR were risk factors for bleeding. Conclusion : We consider it possible that lower TTR values in the LP group were affected by the CYP2C19 genotype. In an aging society, Rabeprazole is safer and more effective as a proton pump inhibitor after open-heart surgery.