Immune checkpoint inhibitor (ICI)-based combination therapy has transformed the treatment of advanced hepatocellular carcinoma (HCC), yet immune-related adverse events (irAEs) remain a serious and potentially fatal complication. We report two cases of severe irAEs following ICIbased therapy for HCC. In Case 1, a man with multimetastatic HCC developed immune-mediated colitis with hemodynamic collapse and multi-organ failure after the second cycle of the STRIDE regimen yet achieved a near-complete oncologic response. In Case 2, a patient who had tolerated 17 cycles of adjuvant atezolizumab (ate) plus bevacizumab (bev) without irAE developed fatal immune-mediated fulminant hepatitis after a single dose of ate+bev reinitiated as first-line therapy for unresectable HCC following recurrence and TACE failure. These cases highlight the unpredictability of irAEs—even in previously tolerant patients—and underscore the importance of early recognition and prompt management.