The literature is scanty regarding the biomechanical effects of different thread configurations on the initial stability of ankle arthrodesis. This study aims to compare the initial stability of tibiotalar fusion site in ankle arthrodesis using cannulated screws with different thread designs. We biomechanically tested under cyclic loading the effects of different screw combinations on the initial stability of ankle arthrodesis. A total of 28 synthetic ankle models were divided into four groups: two partially threaded cancellous screws (group A), partially and fully threaded cancellous screws (group B), a partially threaded cancellous screw with a headless compression screw (group C), and a fully threaded cancellous screw and a headless compression screw (group D). Biomechanical variables including ultimate failure load, initial stiffness, ultimate stiffness, and failure angulation were analyzed. There were no differences in any of the biomechanical variables among the four groups (P = .41 for ultimate failure load, P = .079 for initial stiffness, P = .084 for ultimate stiffness, and P = .937 for failure angulation). Combinations of different cannulated screws showed similar results in terms of the stability and stiffness of the tibiotalar fusion site.