While it is widely recognized that older adults, adults with chronic medical conditions (CMC), and adults with immunocompromising conditions (IC) are at increased risk of lower respiratory tract illness (LRTI), evidence of the magnitude of increased risk is limited. This study was thus undertaken to characterize rates of hospitalized and ambulatory LRTI among United States (US) adults by age and comorbidity profile. A retrospective cohort design and US healthcare claims database (2016-2019) were employed. Study population included adults aged≥18years and was stratified by age and comorbidity profile (CMC-, CMC+, IC). LRTI was ascertained overall and by pathogen pathogen (e.g., respiratory syncytial virus [RSV]), and was classified by care setting (hospital, emergency department [ED], physician office/hospital outpatient [PO/HO]). Relative rates (RR) of LRTI generally increased with older age across care settings (vs. 18-49years), with the most marked increase for hospitalizations: for LRTI-hospitalized, RRs ranged from 3.3 for 50-64years to 46.6 for≥85years; for LRTI-ED and LRTI-PO/HO, RRs ranged from 1.0 to 2.7 and from 1.3 to 1.5, respectively. Within age groups, LRTI rates were also consistently higher among CMC+and IC adults (vs. CMC- adults). Age-specific RRs of LRTI patients hospitalized due to RSV were largely comparable to overall LRTI; age-specific RRs for other care settings, and RRs for CMC+and IC adults (vs. CMC- adults), were generally higher for LRTI due to RSV. Incidence of LRTI, including that due to RSV, especially for events requiring acute inpatient care, is markedly higher among older adults and adults of all ages with CMC or IC.