Various neuromuscular disorders such as spinal cord injury, Charcot-Marie-Tooth disease and poliomyelitis lead to calf muscle weakness, which limits the patient's ability to propel their body forward during gait. Their abnormal gait pattern is characterized by increased ankle dorsiflexion, excessive knee flexion during stance and reduced ankle push-off power which leads to decreased walking speed and increased energy cost of gait. To improve walking ability, dorsal leaf spring (DLS) ankle-foot orthoses (AFOs) are often worn that provide stiffness around the ankle joint which is its most important characteristic. Selecting optimal AFO stiffness is important because it can substantially reduce the net metabolic cost of gait, while improper AFO stiffness can lead to discomfort, fatigue and overall reduced activity. Experimental data shows that the effect of AFOs is dependent on the individual characteristics of the patients, such as level of muscle weakness, spasticity and body mass. Despite the importance of AFO stiffness, empirically determining the stiffness of the applied AFO remains time-consuming and ad hoc. This master thesis aims to uncover the mechanism relating AFO stiffness to the metabolic cost of transport (CoT) as observed in experimental trends from individuals with calf muscle weakness. We used predictive forward musculoskeletal simulations to reproduce the experimental trends and analyzed our simulations to explain the relationship between AFO stiffness and metabolic CoT. The predicted optimal AFO stiffness was within 1 Nm/deg of the patient's experimentally measured one. From the experimentally observed effects, all kinematic and kinetic trends were predicted within 0.5-2.5 SD from the mean of the experimental slopes of all patients' results. Moreover, the differences between the slopes of the simulation results were mostly lower compared to the modelled patient's individual experimental slopes than compared to the experimental slope of the group average results. We identified a reduction in the vasti muscle metabolic cost due to larger external knee extension moments with increasing AFO stiffness as the main mechanism resulting in the net metabolic CoT trend. Limitations on translating our findings to patient behavior include: modelled calf muscle strength, where the model may be significantly stronger or weaker than the patient, and the relative importance of metabolic cost minimization to other goals during walking, such as minimizing the loading rate at heel strike.