PurposeStrenuous running triggers the coordination of pro- and anti-inflammatory, as well as immunoregulatory cytokines, which are upregulated in response to inflammatory stimulus and thus considered a precursor to overuse injury. The aim of this study was to correlate injury risk to footwear stiffness normalized against each runner's weight, i.e. the midsole's ability to resist deformation in response to the applied force. Materials and methodsExperienced runners participated in a 2h 15 min intensity-controlled run, averaging 85 % of their threshold heart rate. Venous blood, collected in the field prior to and immediately after the race, was subjected to multi-parameter flow cytometry, to monitor the plasma levels of interleukin (IL)-2, IL-6 and tumor necrosis factor alpha (TNFα). Footwear stiffness was determined utilizing an automated drop test, recreating footfall pattern, impact speed and weight of each runner. Plasma level increase was analyzed for each cytokine, using one-way ANOVA and the data associated to footwear stiffness through the calculation of Pearson correlation coefficient. ResultsOnly IL-6 levels exhibited a statistical significant increase pre-to post-race, corresponding to F (1,8) = 24.0417 with a critical value of 4.4139. The increase in IL-6 levels was also found to produce a strong correlation to footwear stiffness, expressed in a Pearson coefficient of r (8) = 0.79 at ρ = 0.0063 (P < 0.05). ConclusionThe significant increase in pro-inflammatory markers, such as IL-6 which are associated with injury, would suggest that runners using compliant footwear are at lower risk of overuse injury than the ones running on stiffer midsoles.