The purpose of this study was to investigate the effects of a proposed strength and agility training program of adolescents with Down syndrome. Ninety-two adolescents were recruited and evenly randomized to two intervention groups (exercise group vs. control group). The mean age for the exercise and the control group was 10.6 plus or minus 3.2 and 11.2 plus or minus 3.5 respectively. The exercise training program consisted of a 5-min treadmill exercise and one 20-min virtual-reality based activity administered three times a week for 6 weeks. Pre- and post-test measures were taken for muscle strength and agility performance. The measured muscle included hip extensor, hip flexor, knee extensor, knee flexors, hip abductors, and ankle plantarflexor. A handheld dynamometer was used to measure the lower extremities muscle strength, and agility performance was assessed by the strength and agility subtests of the Bruininks-Oseretsky Test of Motor Proficiency-Second Edition. The exercise group had significant improvements in agility (p = 0.02, d = 0.80) and muscle strength of all muscle group (all p's less than 0.05, d = 0.51-0.89) assessed in comparison to the control group after the 6-week intervention. Knee muscle groups including both flexors and extensors had the greatest gains among all the muscles measured. A short-term exercise training program used in this study is capable of improving muscle strength and agility performance of adolescents with DS. (Contains 3 tables and 1 figure.)