PURPOSE: Childhood cancer survivors (CCSs) are at risk for physical disability. The aim of this investigation was to characterize and compare physical performance among CCSs and a group of siblings age < 18 years and determine if diagnosis, treatment, and physical activity levels were associated with lower performance scores. METHODS: CCSs >/= 5 years from diagnosis and a sibling comparison group were recruited and evaluated for strength, mobility, and fitness. Physical performance measures were compared in regression models between survivors and siblings by diagnosis and among survivors by treatment exposures and physical activity levels. RESULTS: CCSs (n = 183; mean age +/- standard deviation [SD], 13.5 +/- 2.5 years; 53% male) scored lower than siblings (n = 147; mean age +/- SD, 13.4 +/- 2.4 years; 50% male) on lower-extremity strength testing, the timed up-and-go (TUG) test, and the 6-minute walk (6MW) test, despite reporting similar levels and types of habitual physical activity. The lowest scores were prevalent among survivors of CNS tumors and bone and soft tissue sarcomas on strength testing (score +/- SD: CNS tumors, 76.5 +/- 4.7; sarcoma 67.1 +/- 7.2 v siblings, 87.3 +/- 2.4 Newton-meters quadricep strength at 90 degrees per second; P = .04 and .01, respectively) and among CNS tumor survivors on the TUG (score +/- SD: 5.1 +/- 0.1 v siblings, 4.4 +/- 0.1 seconds; P < .001) and 6MW tests (score +/- SD: 533.3 +/- 15.6 v siblings, 594.1 +/- 8.3 m; P < .001). CONCLUSION: CCSs may have underlying physiologic deficits that interfere with function that cannot be completely overcome by participation in regular physical activity. These survivors may need referral for specialized exercise interventions in addition to usual counseling to remain physically active.