Background: Influenza, the most important viral infection affecting older adults, produces a substantial burden in health care costs, morbidity, and mortality. Influenza vaccination remains the mainstay in prevention and is associated with reduced rates of hospitalization, stroke, heart attack, and death in non-institutional older adult populations. Influenza vaccination produces considerably lower antibody response in the elderly compared to young adults. Four-fold higher vaccine antigen (high-dose) than in the standard adult vaccine (standard-dose) elicits higher serum antibody levels and antibody response in ambulatory elderly., Purpose: To describe the design considerations of a large clinical trial of high-dose compared to standard-dose influenza vaccine in nursing homes and baseline characteristics of participating nursing homes and long-stay (more than 90 days) residents over 65 years of age., Methods: The high-dose influenza vaccine intervention trial is multifacility, cluster randomized controlled trial with a 2×2 factorial design that compares hospitalization rates, mortality, and functional decline among long-stay nursing home residents in facilities randomized to receive high-dose versus standard-dose influenza vaccine and also randomized with or without free staff vaccines provided by study organizers. Enrollment focused on nursing homes with a large long-stay resident population over 65 years of age. The primary outcome is the resident-level incidence of hospitalization with a primary diagnosis of pulmonary and influenza-like illness, based upon Medicare inpatient hospitalization claims. Secondary outcomes are all-cause mortality based upon the vital status indicator in the Medicare Vital Status file, all-cause hospitalization directly from the nursing home Minimum Data Set discharge records, and the probability of declining at least 4 points on the 28-point Activities of Daily Living Scale., Results: Between February and September 2013, the high-dose influenza vaccine trial recruited and randomized 823 nursing homes. The analysis sample includes 53,035 long-stay nursing home residents over 65 years of age, representing 57.7% of the participating facilities' population. Residents are mainly women (72.2%), white (75.5%), with a mean age of 83 years. Common conditions include hypertension (79.2%), depression (55.1%), and diabetes mellitus (34.4%). The prevalence of circulatory and pulmonary disorders includes heart failure (20.5%), stroke (20.1%), and asthma/chronic obstructive pulmonary disease (20.2%)., Conclusions: This high-dose influenza vaccine trial uniquely offers a paradigm for future studies of clinical and programmatic interventions within the framework of efforts designed to test the impact of changes in usual treatment practices adopted by health care systems., Trial Registration: NCT01815268., (© The Author(s) 2016.)