This article describes the study design, methodological considerations, and demographic characteristics of a phase III RCT to determine if 1) constraint-induced therapy (CI therapy) can be applied with therapeutic success 3 to 9 months after stroke across different sites, 2) gains that might occur persist over 2 years, 3) initial level of motor ability determines responsiveness to CI therapy, and 4) the treatment effect differs between those treated before 9 months and after 1 year. Six sites will screen and recruit poststroke survivors stratified on initial level of motor ability and after randomization allocate participants to immediate or delayed intervention. Primary outcomes include a laboratory-based measure of function (Wolf Motor Function Test [WMFT]) and a real-world participant-centered functional use measure (Motor Activity Log [MAI]). Secondary outcomes concern function, behavior, and compliance. This is the first multisite, single-blind RCT of a formal training intervention for upper extremity rehabilitation in subacute stroke in the United States.