Study Design Controlled laboratory study. Background Body-weight-support (BWS) running is increasing in popularity, despite limited evidence of its effects on running mechanics. Objectives To determine the effect of increasing BWS on lower-limb biomechanics during lower-body positive-pressure (LBPP) treadmill running. Methods Fourteen male recreational runners completed 15 randomized trials on an LBPP treadmill at 5 levels of BWS and 3 velocities (1-minute trials with 3-minute recovery). Knee and ankle kinematic data were recorded continuously via electrogoniometry. Synchronous in-shoe plantar-pressure data identified stride onset and quantified foot-segment forces. Data were recorded during the final 30 seconds of each trial and averaged over 10 consecutive stride cycles. Results Higher levels of BWS resulted in significantly (P<.001) increased stride duration, reduced stride frequency, and reduced ground contact time (GCT). In addition, normalized GCT (GCT/stride duration) was significantly reduced (P<.001), indicating increased flight time. Increasing BWS resulted in significant reductions (P<.001) in peak knee flexion and dorsiflexion and reduced overall knee and ankle range of motion during the stance phase. Conclusion Running on an LBPP treadmill alters lower-limb kinematics, resulting in reduced ankle and knee joint range of motion. In addition, increased BWS alters stride characteristics, resulting in shorter GCT and longer flight time. Clinicians must be aware of lower-limb kinematic alterations to provide safe and effective parameters for rehabilitation involving LBPP treadmills. J Orthop Sports Phys Ther 2016;46(9):784–793. doi:10.2519/jospt.2016.6503