BACKGROUND: Individuals with chronic lung disease (CLD) face an increased risk of influenza-related complications and mortality, and seasonal vaccination is recommended. Limited evidence exists on the effectiveness of high-dose (HD-IIV) vs. standard-dose (SD-IIV) inactivated influenza vaccines in this population. METHODS: DANFLU-1 trial was a pragmatic, open-label, randomized trial comparing HD-IIV vs. SD-IIV in adults aged 65-79 years during the 2021/2022 influenza season. Vaccines were allocated 1:1. CLD was identified using ICD-10 codes. The prespecified outcomes were hospitalizations due to pneumonia or influenza, respiratory, cardiovascular, cardiorespiratory, and all-cause hospitalizations, and mortality. RESULTS: The study population included 12,477 participants (mean age 71.7 ± 3.9 years, 47 % female), of whom 850 (6.8 %) had CLD. Hospitalization rates for all outcomes were significantly higher among participants with CLD. HD-IIV was associated with a lower risk of hospitalization for pneumonia or influenza (HR 0.36 (CI: 0.17-0.73); no CLD: HR 0.22 (CI: 0.08-0.57); CLD: HR 0.95 (CI: 0.28-3.30); p for interaction = 0.064), respiratory hospitalization, and all-cause mortality, and a lower incidence rate of all-cause hospitalization. Effect estimates were less favorable for HD-IIV compared to SD-IIV among CLD patients in preventing respiratory disease hospitalization and all-cause mortality. CONCLUSION: In this prespecified analysis of the DANFLU-1 randomized trial of HD-IIV vs. SD-IIV, trends suggested that among participants with CLD, the benefit of HD-IIV may be attenuated compared with those without CLD, particularly in relation to respiratory disease hospitalization and all-cause mortality. Given the small sample size, these results should be considered hypothesis-generating and require further investigation. TRIAL REGISTRATION: ClinicalTrials.gov: NCT05048589.