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The purpose of this study was to investigate the acute effects of progressive fatigue on the parameters of running mechanics previously associated with tibial stress fracture risk.Twenty-one trained male distance runners performed three sets (Pre, Mid, and Post) of six overground running trials at 4.5 m·s−1 (±5%). Kinematic and kinetic data were collected during each trial using a 12-camera motion capture system, force platform, and head and leg accelerometers. Between tests, each runner ran on a treadmill for 20 min at their corresponding lactate threshold (LT) speed. Perceived exertion levels (RPE) were recorded at the third and last minute of each treadmill run.RPE scores increased from 11.8 ± 1.3 to 14.4 ± 1.5 at the end of the first LT run and then further to 17.4 ± 1.6 by the end of the second LT run. Peak rearfoot eversion, peak axial head acceleration, peak free moment and vertical force loading rates were shown to increase (P < 0.05) with moderate–large effect sizes during the progression from Pre to Post tests, although vertical impact peak and peak axial tibial acceleration were not significantly affected by the high-intensity running bouts.Previously identified risk factors for impact-related injuries (such as tibial stress fracture) are modified with fatigue. Because fatigue is associated with a reduced tolerance for impact, these findings lend support to the importance of those measures to identify individuals at risk of injury from lower limb impact loading during running.