Background: Systemic therapy is one of the most important treatment modalities for unresectable hepatocellular carcinoma (HCC). At present, six regimens, except durvalumab plus tremelimumab, are reimbursable for the treatment of HCC in Japan. In clinical practice, there are various patient backgrounds and patterns in the treatment sequence of systemic therapy. Therefore, a prospective, observational, large-scale multicenter study of systemic therapy for HCC (PRISM) was conducted to establish real-world evidence from real-world data in Japan. Methods: Patients with histologically or clinically diagnosed HCC, with no prior systemic therapy, with written informed consent were consecutively enrolled into the study. The primary endpoint is overall survival, and the secondary endpoints are the progression-free survival, time-to-treatment failure, grade 3-4 adverse events, and proportion of transition to subsequent treatment; all endpoints are calculated by each regimen/treatment line. The planned sample size is 1,000 patients with an enrollment and follow-up period of 2 years each. Clinical trial registration: UMIN000040488. Results: From August 2020 to July 2022, the enrollment of 1,000 patients was completed in 42 participant hospitals in Japan. As of Sep 2022, the 1000 patients’ background data have been collected. The median age with range was 73 years (30-93). ECOG performance status was 0 in 612 patients (77.9%), and Child-Pugh score was 5 points in 358 (50.2%) and 6 in 226 (31.7%). BCLC stage was B in 277 patients (36.9%) and C in 391 patients (52.1%). 210 patients (26.8 %) and 207 patients (26.4%) had portal vein tumor thrombosis and extrahepatic metastasis, respectively. The median AFP level was 33 ng/mL (range: 1.1- 524878.9). As first-line therapy, atezolizumab plus bevacizumab was selected in 650 (82.5%), lenvatinib in 116 (14.7%), and sorafenib in 15 (1.9%) patients. Conclusions: The analysis of these real-world data of systemic therapy for patients with unresectable HCC could help clarify the treatment outcomes in clinical practice, and is expected to be broadly applicable to real-world evidence in all Japan. Clinical trial information: UMIN000040488.