Background: Tyrosine kinase inhibitors (TKIs) are considered to have effects on portal collateral circulation with portal hypertension. According to previous small sample clinical reports, short-term administration of sorafenib might have an effect of decreasing portal venous pressure, while lenvatinib aggravated portal hypertension. Long-term effects of TKIs on portal pressure are still unclear. Therefore, We conducted a prospective cohort study to explore the efficacy of different TKIs for portal circulation in patients with advanced hepatocellular carcinoma. Methods: 27 Child-Pugh class A or B patients with advanced HCC were enrolled in this study, 13 patients received lenvatinib, 7 patients sorafenib, and 7 patients regorafenib. Changes of portal hemodynamic parameters were measured by duplex Doppler ultrasonography, including portal venous area (PVA), portal venous flow velocity (PVV) and congestion index (CI) before and after administration of TKIs for an average 40-50 days. Results: In both regorafenib and sorafenib cohorts, PVA decreased after treatment, although the difference was not significant. PVF significantly reduced in sorafenib cohort (24.96±5.60 vs. 15.46±4.50, P= 0.014) and regorafenib cohort (21.43±2.09 vs. 16.01±1.28, P= 0.024), therefore CI significantly increased in sorafenib cohort (0.060±0.042 vs. 0.088±0.040, P= 0.046) and regorafenib cohort (0.068±0.032 vs. 0.090±0.030, P= 0.043). In lenvatinib, both PVA and PVF have no significant change, while CI increased significantly (0.057±0.027 vs. 0.074±0.040, P= 0.030). Conclusions: In this study, TKIs showed different effects on portal hemodynamic change in advanced HCC. Large sample and long time follow-up research will be necessary to verify their clinical and mechanism effects.