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To assess the impact of lower-leg muscle activity during the stance phase of running on the development of medial tibial stress syndrome (MTSS), in 123 healthy participants (18.2 ± 0.8 years), dynamic and static foot posture, and soleus and tibialis anterior muscle activity during the stance phase of running were measured before a 17-week track- and field-course. After the course, MTSS was identified in 20.5% of the participants. MTSS participants had a higher body mass (ES = 1.13), body mass index (BMI) (ES = 1.31), lower previous vigorous physical activity level (ES = 0.84) and VO_2max (ES = 0.61), greater dynamic foot pronation (ES = 0.66), higher soleus peak EMG amplitude during the absorption (ES = 0.60) and propulsion phases (ES = 0.56) of running, and a history of MTSS (OR = 6.38) (p < 0.05). Stepwise logistic regression showed BMI, dynamic foot index, soleus peak EMG amplitude during propulsion …