BACKGROUND: Bilateral plantarflexor muscle weakness is a common impairment in many neuromuscular diseases. However, the way in which severity of plantarflexor weakness affects gait in terms of walking energy cost and speed is not fully understood. Predictive simulations are an attractive alternative to human experiments as simulations allow systematic alterations in muscle weakness. However, simulations of pathological gait have not yet been validated against experimental data, limiting their applicability. RESEARCH QUESTION: Our first aim was to validate a predictive simulation framework for walking with bilateral plantarflexor weakness by comparing predicted gait against experimental gait data of patients with bilateral plantarflexor weakness. Secondly, we aimed to evaluate how incremental levels of bilateral plantarflexor weakness affect gait. METHODS: We used a planar musculoskeletal model with 9 degrees of freedom and 9 Hill-type muscle-tendon units per leg. A state-dependent reflex-based controller optimized for a function combining energy cost, muscle activation squared and head acceleration was used to simulate gait. For validation, strength of the plantarflexors was reduced by 80 % and simulated gait compared with experimental data of 16 subjects with bilateral plantarflexor weakness. Subsequently, strength of the plantarflexors was reduced stepwise to evaluate its effect on gait kinematics and kinetics, walking energy cost and speed. RESULTS: Simulations with 80 % weakness matched well with experimental hip and ankle kinematics and kinetics (R > 0.64), but less for knee kinetics (R < 0.55). With incremental strength reduction, especially beyond a reduction of 60 %, the maximal ankle moment and power decreased. Walking energy cost and speed showed a strong quadratic relation (R2>0.82) with plantarflexor strength. SIGNIFICANCE: Our simulation framework predicted most gait changes due to bilateral plantarflexor weakness, and indicates that pathological gait features emerge especially when bilateral plantarflexor weakness exceeds 60 %. Our framework may support future research into the effect of pathologies or assistive devices on gait.