The purpose of this study was to determine if fatigue-related changes in biomechanics derived from an inertial measurement unit (IMU) placed at the center of mass (CoM) are reliable day-to-day. Sixteen runners performed two runs at maximal lactate steady state (MLSS) on a treadmill, one run 5% above MLSS speed, and one run 5% below MLSS speed while wearing a CoM-mounted IMU. Trials were performed to volitional exhaustion or a specified termination time. IMU features were derived from each axis and the resultant. Feature means were calculated for each subject during non-fatigued and fatigued states. Comparisons were performed between the two trials at MLSS and between all four trials. The only significant fatigue state × trial interaction was the 25th percentile of the results when comparing all trials. There were no main effects for trial for either comparison method. There were main effects for fatigue state for most features in both comparison methods. Reliability, measured by an intraclass coefficient (ICC), was good-to-excellent for most features. These results suggest that fatigue-related changes in biomechanics derived from a CoM-mounted IMU are reliable day-to-day when participants ran at or around MLSS and are not significantly affected by slight deviations in speed.