Background: In the Phase 3 HIMALAYA study (NCT03298451) in uHCC, STRIDE (Single T Regular Interval D) significantly improved overall survival versus sorafenib (S) and had manageable safety (Abou-Alfa et al. NEJM Evid 2022). STRIDE is approved for uHCC in the United States and Japan and is recommended for approval by the European Medicines Agency. In this exploratory post hoc analysis, we assessed temporal patterns of imAEs for the STRIDE regimen in HIMALAYA. Methods: Safety was assessed in participants (pts) who received ≥1 dose of STRIDE (T 300 mg [one dose] plus D 1500 mg once every 4 weeks) or S (400 mg twice daily). Treatment causality was investigator-assessed. imAEs were defined as AEs of special interest associated with drug exposure and consistent with an immune-mediated mechanism of action for which no alternate etiology was clear. Safety was summarized descriptively overall and at specific time points after the start of treatment. Results: In total, 388 (STRIDE) and 374 (S) pts were included in the safety analysis. Median (range) duration of exposure was 5.5 (0.4–41.9) months for STRIDE (D exposure in STRIDE) and 4.1 (0.1–38.6) months for S. Any grade treatment-related AEs (TRAEs) and Grade 3 or 4 TRAEs were less frequent for STRIDE (75.8% and 25.8%, respectively) versus S (84.8% and 36.9%, respectively). Any grade imAEs and max Grade 3 or 4 imAEs occurred in 35.8% and 12.6% of pts, respectively for STRIDE. Any grade imAEs and max Grade 3 or 4 imAEs with STRIDE occurred at all time points assessed and were most likely to occur within the first three months after treatment. For STRIDE, any grade imAEs of gastrointestinal disorders and skin and subcutaneous tissue disorders were most common within the first month after treatment (3.9% and 3.1%, respectively), whereas any grade imAEs of endocrine disorders were most common between >1 and ≤2 months (6.7%). Conclusions: In HIMALAYA, AEs with STRIDE were manageable and generally low grade. Any grade TRAEs and Grade 3 or 4 TRAEs were less frequent for STRIDE versus S. Although imAEs with STRIDE could occur at any time, most were observed within the first three months after treatment. These findings continue to support STRIDE for the treatment of uHCC. Clinical trial information: NCT03298451.