It has been proposed that activation of the sympathetic nervous system causes a rightward shift in the renal autoregulatory curve such that renal blood flow is critically dependent on renal perfusion pressure and that this contributes to the development of the hepatorenal syndrome. The aims of the study were to determine the relationship of renal blood flow and renal perfusion pressure in patients with liver cirrhosis and the effect on renal hemodynamics following insertion of a transjugular intrahepatic portosystemic shunt (TIPS). Methods: Fifty-six patients were recruited into groups (1) with no ascites, (2) with diuretic-responsive ascites, (3) with intractable ascites, (4) with type II hepatorenal syndrome, and (5) requiring a TIPSs for refractory ascites. We measured cardiac hemodynamics, renal blood flow, renal perfusion pressure, and portal pressure and norepinephrine levels and mathematically modeled the renal autoregulatory curve. Results: Renal blood flow correlated with renal perfusion pressure (r2 = 0.78; P < .001) and inversely with the hepatic venous pressure gradient (r2 = 0.61; P < .0001) and plasma norepinephrine levels (r2 = 0.78; P < .0001). Norepinephrine levels increased with increasing disease severity, and this was associated with a rightward and downward shift of the renal blood flow/renal perfusion pressure autoregulatory curve. TIPS insertion reduced portal pressure and plasma norepinephrine levels (P < .001), and the renal blood flow/renal perfusion pressure curve was shifted upward. Conclusions: The relationship between renal blood flow and renal perfusion pressure involves a critical interplay between the sympathetic nervous system and the kidney. TIPS insertion decreases sympathetic activation and improves renal function through positive effects on renal blood flow autoregulation.