Ascites is a frequent complication of cirrhosis that accounts for over 75% of episodes of ascites. Patients with cirrhotic ascites have marked splanchnic vasodilation and arterial hypotension with subsequent activation of vasoconstrictive and anti-natriuretic mechanisms. One of the most serious complications in cirrhotic patients with ascites is the occurrence of refractoriness that is the inability to resolve ascites by the standard medical treatment. The aim of this study is to evaluate the effects of etilefrine on systemic hemodynamics, renal function and control of ascites in chronic hepatitis C (CHC) patients with cirrhotic refractory ascites receiving standard medical treatment (SMT) with low sodium diet and maximal diuretic doses of 160 mg/day of furosemide and 400 mg/day of spironolactone. A total of 50 CHC patients with cirrhotic refractory ascites were prospectively studied after 1 month administration of SMT (n = 25) or SMT plus etilefrine (n = 25), in a randomized controlled study. A significant increase in 24-h urinary output, urinary sodium excretion, mean arterial pressure (MAP), and decrease in body weight, plasma ennin activity and plasma aldosterone concentration (P < 0.05) was noted after 1 month in the SMT/etilefrine group. Furthermore, the effective diuretic doses and the need for large-volume paracentesis were significantly reduced in the SMT/etilefrine group compared to the SMT group after 1 month of therapy. No significant changes in the aforementioned parameters were noted in the SMT group, except that MAP was significantly decreased. There was no significant change in the score of the Model for End-stage Liver Disease (MELD) in the SMT/etilefrine group; however, there was significant deterioration in the MELD score in the SMT group. These results suggest that the addition of etilefrine to SMT improves the systemic hemodynamics and enhances water and sodium excretion, providing better control in patients with refractory cirrhotic ascites treated with SMT alone.