Background: Cabozantinib (CAB) has been approved as 2^nd or later-line worldwide in patients with unresectable hepatocellular carcinoma (u-HCC). There is no data about the relationship between the relative dose intensity (RDI) of CAB and clinical outcome. We investigated the impact of RDI on overall survival (OS) and progression-free survival (PFS) during CAB in real-world practice. Methods: A total of 38 u-HCC patients who received CAB between Jan 2021 and Sep 2022 at our institution were enrolled. Tumor assessments in accordance with RECIST ver1.1 were done using dynamic CT or MRI within 4-8 weeks and every 8-10 weeks thereafter. The RDI of CAB for the first month (1M-RDI) was calculated. Results: The median age was 74 years, and 30 patients were Child-Pugh A. BCLC stage A/B/C were 0/ 11/ 27 patients, and 34 patients were previously received atezolizumab plus bevacizumab. As 2^nd or 3^rd-line, 20 patients received CAB. The median follow-up duration was 7.2 months, and the median PFS was 4.4 months in all patients. The median overall survival (OS) was 16.2 months from the administration of CAB. The objective response rate (ORR) and disease control rate (DCR) was 13.8% and 89.7%. Adverse events (AEs) were observed in all patients, requiring dose reduction in 26 patients (68%) and interruption of CAB in 21 patients (55%). The median 1M-RDI was 35%, and there was no significant difference in PFS between 1M-RDI ≧40% (high 1M-RDI, n=13) and <40% (n=16) (4.1 months vs. 4.7 months, p=0.89). There were no significant differences in age, pretreatment ALBI score, AFP, and major vascular invasion (MVI) between the patients with and without a high RDI. The induction rate of molecular targeted therapies after CAB was 60%. The only significant factor associated with PFS was MVI (HR 0.10, 95%CI 0.02-0.65, p=0.02). In a multivariate analysis, pretreatment ALBI score (HR 5.8, 95% CI 1.2-27.8, P=0.03) and hypertension as AE during CAB (HR 0.29, 95% CI 0.09-0.87, P=0.03) were the significant factors associated with OS. Conclusions: Maintaining a high 1M-RDI of CAB was not associated with OS and PFS in real-world practice. Dose modification is essential for CAB therapy in u-HCC patients.