The current investigation examined the effects of running barefoot and in minimalist footwear on medial tibiofemoral compartment loading, compared to conventional running trainers. Fifteen male runners ran over a force platform in five different footwear conditions (barefoot, Vibram five-fingers (Footwear A), Inov-8 (Footwear B) NikeFree (Footwear C), and running trainer) whilst lower extremity kinematics were examined using a three-dimensional camera system. Medial compartment loading during the stance phase was explored using the knee adduction moment (KAM). In addition, the KAM instantaneous load rate was also calculated. Differences between footwear across the entire stance phase were examined using 1-dimensional statistical parametric mapping, whereas differences in discrete parameters were explored using one-way repeated measures ANOVA. Statistical parametric mapping revealed that Footwear B was associated with a significantly larger KAM compared to the running trainer from 15-20 and 25-30% of the stance phase and also Footwear C from 15-20% of the stance phase. The KAM instantaneous load rate was significantly larger in the barefoot (210.69 Nm/kg/s), Footwear A (200.23 Nm/kg/s) and Footwear B (186.03 Nm/kg/s) conditions in comparison to Footwear C (100.88 Nm/kg/s) and running trainers (92.70 Nm/kg/s). The findings from this study indicate that running barefoot and in minimalist footwear with the least midsole interface may place runners at increased risk of medial compartment knee OA, although further exploration using habitual barefoot / minimalist footwear users is required.