<h3>Introduction</h3> Graft-versus-host disease (GVHD) is a major complicating factor in determining morbidity and mortality following allogeneic stem cell transplant. To prevent GVHD, our institution administers calcineurin inhibitors and low doses of methotrexate (MTX) (5-15 mg/m<sup>2</sup>) on days +1, +3, +6, +11 for GVHD prophylaxis. Proton pump inhibitors (PPIs) are used for the treatment of gastroesophageal reflux disease, pyrosis, and/or peptic ulcer disease. PPIs have been shown to inhibit the ATP-binding cassette drug transporter Breast Cancer Resistance Protein's (BCRP/ABCG2) ability to excrete methotrexate into the urine in a concentration-dependent manner. Delayed excretion of methotrexate can lead to adverse events such as renal impairment, increased severity of mucositis, and increased infection rates. <h3>Objectives</h3> The purpose of this retrospective, single center study is to assess the clinical outcomes of patients receiving MTX and PPIs compared to MTX and no PPI for GVHD prophylaxis. <h3>Methods</h3> A single-site retrospective analysis of patients 18 years of age or older who underwent allogeneic stem cell transplantation from 2013 to 2018. Only patients that received methotrexate for GVHD prophylaxis were included. Cases were identified from clinical databases and were divided into two cohorts, those on PPIs, and those not on PPIs (no-PPI). The primary endpoint was grade of mucositis in each cohort. Secondary endpoints were total parenteral nutrition (TPN) use, need for patient controlled analgesia (PCA), time to engraftment of absolute neutrophil count (ANC) and hospital length of stay (LOS). <h3>Results</h3> 284 cases were identified, 119 (42%) patients were on a PPI at the time of MTX administration. The median age of patients on PPI was younger than those not on PPI (60 vs 54 p <0.0001). There were no differences in sex, BSA, conditioning regimen intent, dose of MTX, degree of match, or stem cell source. Patients on PPI had a higher incidence of grade 1-4 mucositis compared to no-PPI (Table 1) and a higher percentage of grade 3-4 mucositis (Figure 1). Patients on PPIs had a higher incidence of TPN use and need for PCA. Use of PPI did not increase the time to ANC engraftment or LOS. <h3>Conclusions</h3> The concurrent use of PPIs and MTX was associated with a higher incidence and severity of mucositis with increased need for PCA, and TPN. This study was limited by retrospective review. Grading of mucositis was based on clinician assessment and documentation. This study raises the question if PPIs should be discontinued or patients transitioned to a histamine blocker prior to MTX administration to improve severity of mucositis and reduce costs associated with TPN/PCA use.