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Prader–Willi syndrome (PWS) is a complex, rare neurobehavioral syndrome characterized by excessive fat, hypotonia, poor motor skills, and behavioral and cognitive disabilities. We tested the effectiveness of a home-based physical activity (PA) intervention led by parents in youth with obesity with and without PWS to increase moderate-to-vigorous PA (MVPA) and gross motor proficiency.Participants were 111 youth age 8 to 16 yr (45 with PWS and 66 without PWS, but categorized as obese). A parallel design was used with the control group (C) receiving the intervention after serving as control. Intervention participants (I) completed a PA curriculum 4 d·wk−1 for 24 wk including warm-up exercises, strengthening exercises, and playground games 2 d·wk−1 and interactive console games 2 d·wk−1 guided by their parents. Pre–post outcomes (baseline to 24 wk) included MVPA (7-d accelerometry) and motor proficiency including upper limb coordination, bilateral coordination, balance, running speed and agility, and muscle strength (Bruininks–Oseretsky Test of Motor Proficiency).The intervention led to no change in MVPA (I group, 39.6 vs 38.9 min·d−1; C group, 40.6 vs 38.3 min·d−1). The intervention led to improvements in body coordination (22.3%; P < 0.05), as well as strength and agility (13.7%; P < 0.05). Specifically, the I group showed increases in upper limb coordination (19.1%), bilateral coordination (27.8%), and muscle strength (12.9%; P < 0.05 for all) not observed in the C group: −0.2%, 2.5%, and −3.2%, respectively.This parent-guided PA intervention did not increase PA. However, the intervention led to improvements in gross motor skill competency. Providing families with tools and support can lead to implementation of PA routines that contribute to motor skill proficiency in youth with and without PWS.