Stress fracture is a common musculoskeletal problem affecting athletes and soldiers. Repetitive high bone strains and strain rates are considered to be its etiology. The strain level necessary to cause fatigue failure of bone ex vivo is higher than the strains recorded in humans during vigorous physical activity. We hypothesized that during fatiguing exercises, bone strains may increase and reach levels exceeding those measured in the non-fatigued state. To test this hypothesis, we measured in vivo tibial strains, the maximum gastrocnemius isokinetic torque and ground reaction forces in four subjects before and after two fatiguing levels of exercise: a 2km run and a 30km desert march. Strains were measured using strain-gauged staples inserted percutaneously in the medial aspect of their mid-tibial diaphysis. There was a decrease in the peak gastrocnemius isokinetic torque of all four subjects' post-march as compared to pre-run (p=0.0001), indicating the presence of gastrocnemius muscle fatigue. Tension strains increased 26% post-run (p=0.002, 95 % confidence interval (CI) and 29% post-march (p=0.0002, 95% CI) as compared to the pre-run phase. Tension strain rates increased 13% post-run (p=0.001, 95% CI) and 11% post-march (p=0.009, 95% CI) and the compression strain rates increased 9% post-run (p=0.0004, 95% CI) and 17% post-march (p=0.0001, 95% CI). The fatigue state increases bone strains well above those recorded in rested individuals and may be a major factor in the stress fracture etiology.