The effects of the acute administration of arterial vasoconstrictors on renal plasma flow (RPF) and urinary sodium excretion (UNaV) in cirrhotic patients with ascites with or without hepatorenal syndrome (HRS) are still controversial. As a consequence, vasoconstrictors are not actually used in the treatment of renal sodium retention or HRS in these patients, regardless of the several lines of evidence suggesting that these renal functional abnormalities are related to a marked arterial vasodilation. The lack of an orally available effective arterial vasoconstrictor probably represents a further reason for this omission. Consequently, the present study was made to evaluate the acute effects of the oral administration of midodrine, an orally available α-mimetic drug, on systemic and renal hemodynamics and on UNaV in cirrhotic patients with ascites. Mean arterial pressure (MAP), heart rate (HR), cardiac index (CI), systemic vascular resistance (SVR), left forearm blood flow (LFBF), left leg blood flow (LLBF), RPF, glomerular filtration rate (GFR), UNaV, plasma renin activity (PRA), plasma concentration of antidiuretic hormone (ADH), and the serum levels of nitrite and nitrate (NOx) were evaluated in 25 cirrhotic patients with ascites (17 without HRS and 8 with type 2 HRS) before and during the 6 hours following the oral administration of 15 mg of midodrine. During the first 3 hours after the drug administration, a significant increase in MAP (89.6 ± 1.7 vs. 81.80 ± 1.3 mm Hg; P < .0001) and SVR (1,313.9 ± 44.4 vs. 1,121.2 ± 60.1 dyn · sec · cm−5; P < .0001) accompanied by a decrease in HR (69 ± 2 vs. 77 ± 3 bpm; P < .005) and CI (2,932.7 ± 131.4 vs. 3,152.5 ± 131.4 mL · min−1 · m2 BSA; P < .0025) was observed in patients without HRS. No change was observed in LFBF and LLBF. The improvement in systemic hemodynamics, which was also maintained during the the 3- to 6-hour period after midodrine administration, was accompanied by a significant increase in RPF (541.5 ± 43.1 vs. 385.7 ± 39.9 mL · min−1; P < .005), GFR (93.1 ± 6.5 vs. 77.0 ± 6.7 mL · min−1; P < .025), and UNaV (92.7 ± 16.4 vs. 72.2 ± 10.7 μEq · min−1; P < .025). In addition, a decrease in PRA (5.33 ± 1.47 vs. 7.74 ± 2.17 ng · mL−1 · h; P < .05), ADH (1.4 ± 0.2 vs. 1.7 ± 0.2 pg · mL−1; P < .05), and NOx (33.4 ± 5.0 vs. 49.3 ± 7.3 μmol−1; P < .05) was found. In patients with HRS, the effects of the drug on the systemic hemodynamics was smaller and shorter. Accordingly, regardless of a significant decrease in PRA (15.87 ± 3.70 vs. 20.70 ± 4.82 ng · mL−1 · h; P < .0025) in patients with HRS, no significant improvement was observed in RPF, GFR, or UNaV. In conclusion, the acute oral administration of midodrine is associated with a significant improvement in systemic hemodynamics in nonazotemic cirrhotic patients with ascites. As a result, renal perfusion and UNaV also improve in these patients. By contrast, midodrine only slightly improves systemic hemodynamics in patients with type 2 HRS, with no effect on renal hemodynamics and renal function.