BACKGROUND: Frailty is a risk factor for adverse influenza-related outcomes. We assessed the effectiveness of high-dose inactivated influenza vaccination (HD-IIV) versus standard-dose inactivated influenza vaccination (SD-IIV) according to a frailty score. METHODS: This was a post hoc analysis of the randomized feasibility trial of HD-IIV versus SD-IIV conducted during the 2021-2022 influenza season in older adults aged 65-79 years. We assessed prespecified outcomes, including hospitalizations and deaths, as first and recurrent events. Frailty was defined according to the hospital frailty risk score (HFRS). RESULTS: Among 12 477 included participants (mean age, 71.7 years; 47.1% female), 10 689 (85.7%) were categorized as having low frailty (HFRS <5) and 1784 (14.3%) had intermediate or high frailty (HFRS ≥5). HD-IIV versus SD-IIV was associated with a lower risk of first and recurrent hospitalizations for pneumonia or influenza regardless of the HFRS. For participants with low frailty there were 22 events (hazard ratio [HR], 0.37 [95% confidence interval, .15-.96]) and 25 recurrent events (incidence rate ratio, 0.31 [.11-.84]), and for those with intermediate or high frailty there were 16 events (HR, 0.33 [.11-1.01]) and 18 recurrent events (incidence rate ratio, 0.28 [.09-.92]; P value for continuous interaction with HFRS [Pinteraction] = .92 for first and Pinteraction = .93 for recurrent events). The HFRS modified the association of HD-IIV versus SD-IIV with all-cause mortality (Pinteraction = .02), with an association with reduced risk in participants with low frailty only (43 events, HR, 0.26 [95% confidence interval, .13-.55]). CONCLUSIONS: HD-IIV was associated with a lower risk of first and recurrent hospitalizations for pneumonia and influenza compared with SD-IIV and may be preferred for older adults, irrespective of frailty status. The HFRS modified the association of HD-IIV versus SD-IIV with all-cause mortality.