Background: SOR was the standard first-line treatment for HCC for about a decade until the approval of LEN. Subsequently, atezolizumab + bevacizumab (A+B) were shown to have superior efficacy outcomes. The aim of this study was to compare effectiveness outcomes of HCC patients treated in the SOR era compared to the post-SOR era, when most HCC patients received first-line LEN or A+B. Methods: All HCC patients who started first-line systemic therapy at cancer centres in the Canadian province of Alberta between January 1, 2008 and December 31, 2021 were included in this study. Overall survival (OS), progression-free survival (PFS), and clinician-assessed response rate (RR) were retrospectively analyzed. Since LEN was first available to patients in Canada in August 2018, patients who started first-line systemic therapy between January 2008 to July 2018 were classified as treated in the “SOR era”, while patients treated from August 2018 to December 2021 were classified as being treated in the “post-SOR era”. Results: Of 372 total patients included, 230 were treated in the SOR era and 142 in the post-SOR era. Demographic and clinical characteristics are as follows for the SOR era and post-SOR era groups, respectively: median age was 63 and 64 years, 80% and 81% were male, 24% and 11% were of East Asian ethnicity. Most patients were ECOG 0-1 (85% and 91%), Child-Pugh A (84% and 85%), and ALBI grade 1 or 2 (96% and 98%) prior starting first-line therapy. Most common causes of liver disease included excess alcohol use (24% and 30%), Hepatitis C (37% and 48%), and Hepatitis B (27% and 15%). Most patients had advanced (BCLC C) stage disease in both groups (91% and 87%). Prior to systemic treatment 40% and 33% received TACE, 7% and 9% received TARE, and 3% and 14% received SBRT respectively. See table for first-line treatments received and outcomes. Median treatment duration was 3.2 months and 4.8 months, and median follow-up time was 9.6 and 11.0 months for SOR era and post-SOR era, respectively. Conclusions: In this real-world multicenter retrospective study, patients treated in the post-SOR era, where LEN and A+B were the more common first-line treatments, had superior overall survival, first-line response rates and progression-free survival. This study confirms the real-world progress that has been made in improving outcomes of HCC patients through systemic treatment advancements over the last 15 years.