Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) is one of the leading etiologies of HCC. Recent evidence indicates that MASLD might affect the response to immune checkpoint inhibitors and multi-receptor tyrosine kinase inhibitors in the treatment for unresectable hepatocellular carcinoma (HCC), yet real-world data with accurate pathological diagnosis of MASLD has not been confirmed. Methods: Patients with unresectable HCC who had been pathologically diagnosed with MASLD by liver biopsy and/or hepatectomy and later received treatment with lenvatinib (LEN) or atezolizumab plus bevacizumab (ATZ/Bev) as first-line systemic treatment for HCC were included. Outcomes of treatment with LEN or ATZ/Bev were compared. Results: A total of 48 patients who received LEN (n=26) and ATZ/Bev (n=22) were included. The mean time from pathological diagnosis to the initiation of treatment was not different (LEN 1,542 days, ATZ/Bev 1,260 days; p=0.48). The degree of steatosis, inflammation, ballooning hepatocytes and fibrosis did not differ between LEN and ATZ/Bev. At the initiation of treatment, BCLC stage, albumin–bilirubin grade, and Child–Pugh grade did not differ between LEN and ATZ/Bev. The overall response rate and disease control rate evaluated with modified RECIST criteria were not different between LEN and ATZ/Bev (26.1% and 77.2% for LEN, and 22.7% and 70.8% for ATZ/Bev). Median progression-free survival (PFS) was not different between LEN and ATZ/Bev (266 days vs 287 days, p=0.278). Median overall survival (OS) of LEN tended to be longer than that of ATZ/Bev (1364 days vs 663 days, p=0.081). The potential advantage of LEN in OS was statistically significant in the patients with Child-Pugh score = 5 (P=0.0443). A total of 17 patients received both LEN and ATZ/Bev treatment and order of the treatment did not associate with PFS and OS. Conclusions: Outcomes of LEN and ATZ/Bev treatment for advanced HCC were not different in pathologically confirmed MASLD. Longer OS of LEN than ATZ/Bev was observed in the patients with relatively better liver function, suggesting that LEN might be a suitable first-line treatment for HCC with compensated liver function in the patients with pathologically confirmed MASLD.