Gastrointestinal bleeding (GIB) remains a common and vexing complication of left ventricular assist device (LVAD) support. Recent single-center analyses suggest that ACE inhibitors (ACEi)/angiotensin receptor blockers (ARB) and digoxin may prevent GIB in LVAD patients. Here we evaluate the effect of heart failure (HF) drug therapies on rates of GIB through analysis of the INTERMACS registry database. 13,732 patients who received a continuous-flow LVAD and were on antiplatelet therapy coupled with warfarin anticoagulation at 3 months of pump support were included in the analysis. GIB events beyond 3 months following implant were assessed receipt of ACEi/ARB, beta-blockers (BB), aldosterone antagonists (AA), amiodarone (Amio), digoxin, loop diuretics, and phosphiesterase inhibitors (PDE5) at 3 months of support. Backwards stepwise cox regression was used to control for confounding of each drug class on each other, as well as for clinical variables like age, gender, renal function, HF etiology, and device strategy. Medication use in LVAD patients were BB (65.0%), ACEi/ARB (51.7%), Amio (43.7%), AA (37.9%), and loop diuretics (70.1%) at 3 months of pump support. In patients with available data, PDE and digoxin use were 18.2% and 16.9% respectively. The overall incidence of GIB was 23.7% at 2 years of support. After adjustment for other clinical variables, loop diuretics (HR 1.274, p<0.001) and PDE5 (HR 1.241, p<0.001) use were associated with increased risk GIB, while use of BB (HR 0.871, p=0.006) was associated with lower risk of GIB. ACEi/ARB (HR 1.002, p=0.971), Amio (HR 1.083, p=0.106), AA (HR 0.967, p=0.522) or digoxin (HR 1.087, p=0.169) did not affect GIB rates on LVAD support (Figure). Despite recent reports, ACEi/ARB, AA, Amio, and digoxin use have minimal association with GIB on LVAD support. The heightened risk seen in those on loop diuretics may reflect venous congestion in these patients, while antiplatelet effects of PDE5 could drive the higher risk of GIB.