Injury patterns in distance running may be related to kinematic adjustments induced by fatigue. The goal was to measure changes in lower extremity mechanics during an exhaustive run in individuals with and without a history of iliotibial band syndrome (ITBS). Sixteen recreational runners ran to voluntary exhaustion on a treadmill at a self-selected pace. Eight runners had a history of ITBS. Twenty-three reflective marker positions were recorded by an eight-camera 120 Hz motion capture system. Joint angles during stance phase were exported to a musculoskeletal model (SIMM) with the iliotibial band (ITB) modeled as a passive structure to estimate strain in the ITB. For ITBS runners, at the end of the run: (1) knee flexion at heel-strike was higher than control (20.6 degrees versus 15.3 degrees, p=0.01); (2) the number of knees with predicted ITB impingment upon the lateral femoral epicondyle increased from 6 to 11. Strain in the ITB was higher in the ITBS runners throughout all of stance. Maximum foot adduction in the ITBS runners was higher versus control at the start of the run (p=0.003). Maximum foot inversion (p=0.03) and maximum knee internal rotation velocity (p=0.02) were higher versus control at the end of the run. In conclusion, ITB mechanics appear to be related to changes in knee flexion at heel-strike and internal rotation of the leg. These observations may suggest kinematic discriminators for clinical assessment.