Background: Tyrosine kinase inhibitors (TKI) are currently the recommended treatment option for advanced renal cell carcinoma (aRCC) patient. Previous studies have shown some hepatorenal toxicity of TKI regimens, but differences in toxicity and long-term toxicity of TKIs have rarely been reported. This study aims to compare short- and long-term hepatorenal toxicity differences between pazopanib and sunitinib, and to explore the factors predisposing to hepatorenal toxicity. Methods: COMPARZ study was a randomized phase III non-inferiority study comparing pazopanib and sunitinib in aRCC patients. Patients without liver metastasis and with available alanine transaminase (ALT), aspartate transaminase (AST), and total bilirubin results were enrolled to evaluate the effect of TKI on liver function. Patients with available serum creatinine (Cr), blood urea nitrogen (BUN), urine protein/creatinine ratio (UPC), and creatinine clearance (CrCl) were enrolled to evaluate factors associated with abnormal renal function. Lab indicators were compared between baseline and at months 12, 24, and 36 by paired t-test respectively. Linear mixed models were used to compare the difference in changes between treatment arms. Multivariate logistic regression was performed to examine the factors associated with recorded adverse events of hepatorenal toxicities. Results: Patients with abnormal liver function tests at baseline had higher elevated ALT, AST and total bilirubin levels at 12 months after TKIs treatment compared with patients who had normal baseline results. ALT levels were not significantly different between pazopanib arm and sunitinib arm at 12, 24 and 36 months. However, patients in the sunitinib arm had significantly higher AST levels than the pazopanib arm at 12 months (p = 0.049). There was no significant difference in total bilirubin level between pazopanib and sunitinib arm. Asian race and pazopanib were two factors that was significantly associated with increased risk of developing abnormal liver function. At 12 months, Cr levels were higher in the sunitinib arm compared with the pazopanib arm . BUN levels were lower in the pazopanib arm at 12 months but conversely was higher in the sunitinib arm at 24 months. UPC levels were significantly elevated in both treatment arms at 12 months (p < 0.001) and 24 months (p = 0.008). CrCl levels decreased in both treatment arms, and was more obvious in the sunitinib group at 12 months and 24 months. Notably, male patients, Asian race, high BMI, and sunitinib were risk factors that were significantly associated with abnormal renal function. Conclusions: Compared with sunitinib, pazopanib was associated with a higher risk of hepatoxicity but lower risk of nephrotoxicity. Overall, Asian patients have a higher risk of developing abnormal liver and renal functions after TKI treatment.