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Introduction Immunocompromised individuals have suboptimal COVID-19 vaccine responses and may continue physically distancing to avoid COVID-19. The EAGLE Study aimed to quantify physical distancing behaviours and associations with health-related quality of life (HRQoL) and related measures in immunocompromised adults.Methods EAGLE was a cross-sectional, observational online survey study of US and UK immunocompromised adults, children and those children’s caregivers, with adult analyses reported here. Multichannel enrolment and self-reported data collection occurred from December 2022 to June 2023. Immunocompromising diagnosis confirmation using medical records was requested from a randomly selected subset. Physical distancing (in past 4 weeks) was measured using the Physical Distancing Scale for COVID-19 Avoidance (PDS-C19). HRQoL and related measures were the 12-item Short Form Health Survey version 2 (SF-12v2) (includes Short-Form 6-Dimensions), Quality of Life Disease Impact Scale-7-item (QDIS-7), Direct Measure of Loneliness, EQ-5D-5L, Hospital Anxiety and Depression Scale and Work Productivity and Activity Impairment plus Classroom Impairment Questions: Specific Health Problem (WPAI+CIQ:SHP). Associations between PDS-C19 and HRQoL and related measures were assessed using Pearson correlation, linear regression (potential confounders-adjusted) and preliminary structural equation modelling (SEM).Results 2320 immunocompromised adults fully completed the survey. Confirmation of diagnosis was requested from 27% and confirmed for 90% of responders. 68% of participants reported moderate to high physical distancing. Physical distancing had low correlations with SF-12v2-measured HRQoL domains (range |r|=0.18 to 0.39) and medium correlations with QDIS-7 (r=0.78) and WPAI+CIQ:SHP-measured activity impairment (r=0.68) and presenteeism (r=0.51). In SEM, direct PDS-C19 relationships explained most activity correlations: QDIS, β=0.46 (SE=0.02); activity impairment, β=0.40 (0.02); presenteeism, β=0.29 (0.04). Unstandardised PDS-C19 confounder-adjusted linear regression coefficients were similar to those of SEM.Conclusions Over 3 years after COVID-19 emergence, a disproportionate number of immunocompromised adults reported substantially physically distancing to avoid COVID-19. Higher physical distancing intensities were associated with greater HRQoL impairments, suggesting such challenges coexist as ongoing concerns for immunocompromised adults.