AimDurvalumab plus tremelimumab (Dur/Tre) is a first‐line systemic treatment option for unresectable hepatocellular carcinoma (uHCC). However, the management of severe immune‐mediated adverse events (imAEs) is challenging. Therefore, we investigated the relationship between severe imAEs and antitumor responses in patients with uHCC treated with Dur/Tre.MethodsWe included 157 patients with uHCC treated with Dur/Tre in this multicenter, retrospective study and analyzed the relationship between progression‐free survival (PFS)/antitumor response and severe imAEs requiring high‐dose corticosteroid treatment.ResultsThirty‐two patients (20.4%) developed severe imAEs, including enterocolitis/diarrhea (n = 10), liver injury (n = 9), interstitial lung disease (n = 5), rashes (n = 4), cytokine‐release syndrome/fever (n = 2), pancreatitis (n = 2), and others (n = 4) (median follow‐up period, 6.8 months). Infliximab was administered in six patients with steroid‐refractory enterocolitis. Although the objective response rate (ORR) and disease control rate (DCR) were significantly higher with first‐line therapy than with later‐line therapy (p = 0.026), the frequency of severe imAEs was not significantly different (p = 0.221). The ORR and DCR in patients with and without severe imAEs were 15.6% and 17.6% and 65.6% and 47.2%, respectively, with no significant differences. Five patients with severe imAEs, including rashes and liver injury, showed objective responses (partial response + complete response). Among patients who achieved an objective response, the PFS at 10 months was good (100% and 70.3% with and without high‐dose corticosteroids, respectively).ConclusionsSevere imAEs of Dur/Tre treatment requiring high‐dose corticosteroid treatment did not affect antitumor efficacy, which differed depending on the type of imAEs. Therefore, appropriately managing imAEs is essential to guide sequential treatment.