Perinatal arterial stroke (PAS) includes infants with neonatal arterial ischemic stroke and presumed perinatal arterial stroke and has an estimated incidence of 1 in 1150. The majority will develop hemiparesis, often resulting in lifelong and debilitating disability, including lowered cognition and quality of life. There are no evidence-based forms of rehabilitation designated as standard-of-care for these infants. We propose a Phase III trial to address this lack of evidence-based treatments. The I-ACQUIRE Trial is a rigorous, adequately powered, multi-site randomized controlled trial comparing 2 dosages of a pediatric rehabilitation - known as Infant ACQUIRE - to Usual and Customary treatment (U&CT). Prior studies of I- ACQUIRE show high safety, patient acceptability, and evidence of significant and enduring benefits. Briefly, I- ACQUIRE will be used to treat 8 – 24 mth old infants with PAS in either 3 hrs/day (Moderate Dose) or 6 hrs/day (High Dose), for 5 days/wk for 4 wks. Treatment occurs in a home or natural setting where operant conditioning techniques are applied to achieve goals paced for each infant. I-ACQUIRE includes the core features of pediatric Constraint-Induced Movement Therapy (CIMT). Standardized treatment at all sites is monitored weekly via a Fidelity of CIMT Implementation tool. Clinical Trial Design: 240 infants (N=80/group) will be randomly assigned to: 1) Moderate Dose I-ACQUIRE, 2) High Dose I-ACQUIRE, or 3) U&CT. (N=80). Double-blinded assessments occur at baseline, end of 4 wks of treatment, and 6 mos post-treatment. A Parent Council will be active throughout the trial, supporting NIH's goal of increased stakeholder engagement in clinical trials. The specific aims are: 1) Primary: Determine the efficacy of I-ACQUIRE at 2 dosage levels compared to U&CT to increase upper extremity skills on the hemiparetic side (using a minimal clinically meaningful threshold that is achieved at end of treatment and 6 mos later); 2) Secondary: Determine the efficacy of I- ACQUIRE at 2 dosage levels compared to U&CT to improve use of the hemiparetic upper extremity as an “assisting hand” in bimanual activities; and 3) Exploratory: Explore the association between I-ACQUIRE treatment at Moderate and/or High Doses and the infant's gross motor development and cognition (i.e., potential cross-domain effects of treatment). The Statistical Analysis Plan controls for multiple comparisons; after testing the major study hypotheses, sensitivity analyses will consider factors that may contribute to variation in treatment outcomes. Public Health Impact: Each year, an estimated 3400+ infants in the U.S. have PAS with high likelihood of lifelong impairment in neuromotor and often cognitive functioning resulting in a high cost burden for families, the healthcare system, and society. If I-ACQUIRE proves efficacious, then the field will have the critically needed Phase III confirmatory evidence and the specific clinical protocol needed to transform reh...