To (1) investigate the hypothesis that there is high variability in the reported methods to derive axes and joint orientations from three-dimensional (3D) bone models to (a) perform 3D knee-related leg alignment analysis and (b) define coordinate systems for the femur, tibia and leg and (2) identify underlying principles that might lead to agreement on a universal 3D leg alignment analysis framework. A systematic review of the literature between January 2006 and June 2024 was performed. Articles explicitly reporting methods to derive axes and joint orientations from CT-based 3D bone models for alignment parameters and/or coordinate systems of the femur, tibia and leg were included. Study characteristics and reported methods were extracted and presented as a qualitative synthesis. A total of 93 studies were included. There was high variability in the reported methods to derive axes and joint orientations from 3D bone models. Nevertheless, the reported methods could be categorized into four groups, and several underlying principles of the four groups could be identified. Furthermore, the definitions of femoral and tibial coordinate systems were most frequently based on the mechanical axis (femoral, 13/19 [68%]; tibial, 13/26 [50%]) and a central medial-lateral axis (femoral, 16/19 [84%]; tibial, 12/26 [46%]); no leg coordinate system was reported. Interestingly, of the included studies that reported on leg alignment parameters (76/93, 82%), only a minority reported expressing these in a complete coordinate system (25/76, 33%). There is high variability in 3D knee-related leg alignment analysis. Therefore, universal 3D reference values for alignment parameters cannot yet be defined, and comparison of alignment parameter values between different studies is impossible. However, several underlying principles to the reported methods were identified, which could serve to reach more agreement on a future universal 3D framework for leg alignment analysis. Level I (1).