Background: Combination therapy with isosorbide dinitrate (ISD) and hydralazine (HY) reduces heart failure mortality. The safety and tolerability in individuals requiring maintenance hemodialysis (HD) is unknown. Methods: Single-center, randomized, placebo-controlled, double-blind pilot trial to explore safety and tolerability of ISD/HY in maintenance HD. Participants were randomized to placebo or combination ISD/HY. Dose was escalated over three weeks from ISD 10 mg/HY 10 mg to ISD 40 mg/HY 75 mg three times/day with the maximum tolerated dose maintained for the subsequent 21 weeks. Primary endpoints included adverse events, adverse events precluding further treatment with study medication, serious hypotension (i.e., requiring hospitalization or emergency room visit), and recurrent intra-dialytic hypotension. Efficacy signals included change in mitral annular E' velocity by tissue Doppler echocardiography and change in left ventricular coronary flow reserve (CFR) on positron emission tomography. Results: 17 individuals were randomized to ISD/HY (7) or placebo (N=10). All participants assigned to ISD/HY completed dose escalation to 40/75 mg, but dose reductions were required in 2 participants. No participants discontinued therapy. There were no serious hypotension events. Recurrent intradialytic hypotension was less frequent with ISD/HY (0.47 events/patient-year (PY)) than placebo (1.83 events/patient-year, P=0.04). In contrast, nausea (ISD/HY1.90 events/PY, placebo 0.50 events/PY, P=0.03) was significantly more frequent and headache and diarrhea were numerically but not significantly more frequent with ISD/HY. Adverse events were more frequent with ISD/HY (11.4 events/PY) than placebo (6.31 events/PY). We did not detect between-group differences in the change in E' (P=0.34) -ISD/HY-mean increase of 0.6 cm/S (SD 1.1), placebo-mean decrease of 0.04 cm/S (SD 0.9). Changes in coronary flow reserve were minimal -0.3 (0.2) with ISD/HY and -0.03 (0.5) in the placebo group, P=0.19. Conclusion: ISD/HY appears to be well-tolerated in maintenance HD patients, but headache and gastrointestinal side effects occur more frequently with ISD/HY compared with placebo.