Hepatic arterial infusion chemotherapy (HAIC) has been popular for treating unresectable hepatocellular carcinoma (HCC). However, there are few reports comparing the transradial approach (TRA) and transfemoral approach (TFA) in HAIC.This study aimed to compare the duration of the hepatic artery catheterization, fluoroscopy time (FT), radiation exposure, safety, and quality of life associated with the procedure in patients undergoing HAIC via TRA and TFA.This prospective, single-center, randomized, controlled study included 120 patients with unresectable HCC undergoing HAIC procedures. Patients were randomly assigned to group A (n = 60, TRA-HAIC) or group B (n = 60, TFA-HAIC). The hepatic artery catheterization time, FT, entrance surface dose (ESD), dose area product (DAP), procedure-related complications, and quality of life associated with the procedure were assessed between the two groups. Independent-sample t-test and analysis of variance (ANOVA) were used to assess differences. Statistical significance was set at P < 0.05.HAIC procedures were successfully performed in both groups. The hepatic artery catheterization time (19.35 ± 5.84 vs. 18.93 ± 5.62 minutes, P = 0.837), FT (2.35 ± 2.23 vs. 2.25 ± 2.16 minutes, P = 0.901), ESD (259.32 ± 167.46 vs. 250.56 ± 170.58 mGy, P = 0.449), and DAP (125.37 ± 60.65 vs. 120.56 ± 64.33 Gy.cm3, P = 0.566) were comparable between the two groups. The incidence of artery occlusion (10.0% vs. 0%, P < 0.001) in the TRA group was significantly higher than that in the TFA group. TRA was associated with a statistically significant (P < 0.05) improvement in the quality of life.TRA to HAIC was associated with greater improvement in the quality of life associated with the procedure compared with TFA. Both approaches to HAIC had similar efficiency, safety, radiation exposure, and procedure duration.Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.