BACKGROUND: Bone stress injuries (BSIs) are common in female runners, and recurrent BSI rates are high. Previous work suggests an association between higher impact loading during running and tibial BSI. However, it is unknown whether impact loading and fatigue-related loading changes discriminate women with a history of multiple BSIs. This study compared impact variables at the beginning of a treadmill run to exertion and the changes in those variables with exertion among female runners with no history of BSI as well as among those with a history of single or multiple BSIs. METHODS: We enrolled 45 female runners (aged 18-40 years) for this cross-sectional study: having no history of diagnosed lower extremity BSI (N-BSI, n = 14); a history of 1 lower extremity BSI (1-BSI, n = 16); and diagnosed by imaging, or a history of multiple ( ≥ 3) lower extremity BSIs (M-BSI, n = 15). Participants completed a 5-km race speed run on an instrumented treadmill while wearing an Inertial Measurement Unit. The vertical average loading rate (VALR), vertical instantaneous loading rate (VILR), vertical stiffness during impact via instrumented treadmill, and tibial shock determined as the peak positive tibial acceleration via Inertial Measurement Unit were measured at the beginning and the end of the run. RESULTS: There were no differences between groups in VALR, VILR, vertical stiffness, or tibial shock in a fresh or exerted condition. However, compared to N-BSI, women with M-BSI had greater increase with exertion in VALR (-1.8% vs. 6.1%, p = 0.01) and VILR (1.5% vs. 4.8%, p = 0.03). Similarly, compared to N-BSI, vertical stiffness increased more with exertion among women with M-BSI (-0.9% vs. 7.3%, p = 0.006) and 1-BSI (-0.9% vs. 1.8%, p = 0.05). Finally, compared to N-BSI, the increase in tibial shock from fresh to exerted condition was greater among women with M-BSI (0.9% vs. 5.5%, p = 0.03) and 1-BSI (0.9% vs. 11.2%, p = 0.02). CONCLUSION: Women with 1-BSI or M-BSIs experience greater exertion-related increases in impact loading than women with N-BSI. These observations imply that exertion-related changes in gait biomechanics may contribute to risk of BSI.