PURPOSE: The DANFLU-1 trial suggested lower incidence of hospitalizations for pneumonia and influenza, respiratory disease and all-cause mortality among older adults receiving high-dose (HD-IV) versus standard-dose (SD-IV) influenza vaccine. This study assessed the relative effectiveness of HD-IV versus SD-IV according to comorbidity in elderly individuals. METHODS: This was a post-hoc analysis of the DANFLU-1 randomized controlled feasibility trial of HD-IV versus SD-IV conducted during the 2021-2022 influenza season in adults aged 65-79 years. Outcomes assessed included influenza-related, respiratory, and cardiovascular hospitalizations, and mortality. We tested for effect modification by level of the Charlson Comorbidity Index (CCI) using ICD-10 codes up to 10 years prior to randomization. RESULTS: Of the 12,477 randomly assigned participants (mean age 71.7 ± 3.9 years, 47.1% female), 8,020 (64.3%) had CCI = 0, 3,560 (28.5%) had CCI = 1-2 and 893 (7.2%) had CCI ≥ 3. When comparing HD-IV with SD-IV, hazard ratios of hospitalizations for pneumonia and influenza were similar across CCI groups (HR [95%CI]: 0.15 [0.03-0.68] for CCI = 0, 0.36 [0.11-1.15] for CCI = 1-2, 1.00 [0.25-4.00] for CCI ≥ 3). Comparable patterns were found for hospitalizations for respiratory disease (0.46 [0.17-1.20] for CCI = 0, 0.67 [0.32-1.39] for CCI = 1-2, 0.66 [0.24-1.87] for CCI ≥ 3) and all-cause mortality (0.28 [0.09-0.86] for CCI = 0, 0.70 [0.30-1.63] for CCI = 1-2, 0.57 [0.24-1.36] for CCI ≥ 3). There was no statistical evidence of effect modification by CCI for any outcome. CONCLUSIONS: The lower incidences of clinical outcomes for HD-IV compared to SD-IV were not significantly modified by CCI. The potential benefit of HD-IV versus SD-IV may therefore be applicable regardless of comorbidity burden. Further research is required to confirm these findings.