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Purpose Cumulative load has become a popular metric in running biomechanics research to account for potential spatiotemporal changes associated with different locomotion strategies. This study investigated how incorporating mechanical fatigue principles into Achilles tendon cumulative load measurements affected their relationship with running speed. Methods Achilles tendon forces and strains were estimated from a dynamometry/ultrasound session followed by a motion capture session, where participants ran at three speeds. Three cumulative measures of increasing complexity were calculated using Achilles tendon force/strain: 1) cumulative load, defined as the product of the stance phase time integral of Achilles tendon force/strain and the stride count for 1 km of running; 2) cumulative damage, which accounted for the nonlinear relationship between load magnitude and fatigue life by exponentially weighting the time integral of Achilles tendon force/strain before multiplication with stride count; and (3) the probability of fatigue failure, which expanded upon the cumulative damage measure of Achilles tendon strain by fitting a probabilistic Weibull model to existing fatigue life data to account for the inherent variability that exists in the fatigue life of biological samples. Results Cumulative load measures significantly decreased with running speed, whereas the cumulative damage and probabilistic measures either increased or did not change significantly with running speed. Conclusions The choice of cumulative metric has an important influence on the interpretation of overuse injury risk with changes in running speed. Although cumulative load metrics certainly provide meaningful information about the load experienced over a given distance, they do not account for the tissue damage incurred by such load. Cumulative load metrics should therefore be interpreted with caution when making inferences to overuse injury risk.