The purpose of the present work was to describe and assess the performance on two selected subjects of a new method for the compensation of soft tissue artifact on knee rotations and translations during the execution of step up/down, sit-to-stand/stand-to-sit, and flexion against gravity. Soft tissue artifact has been recognized as the most critical source of error in gait analysis data. Its propagation strongly affects joint angles, in particular those characterized by a small range of motion, such as knee ab/adduction and internal/external rotation. This may be critical in the exploitation of gait analysis data for clinical decisions. The proposed method is based on the flexion/extension angle interpolation of two anatomical landmark calibrations taken at the extremes of motion. Its performance on knee rotation and translations was tested on a kinematics data-set obtained by the synchronous combination of traditional stereophotogrammetry and 3-D fluoroscopy. The newly proposed method was extremely effective on the compensation of soft tissue artifact propagation to knee rotations, in particular mean values of the root mean square error on ab/adduction and internal/external rotation angles decreased from 3.7 degrees and 3.7 degrees to 1.4 degrees and 1.6 degrees, respectively, with respect to single calibration. Mainly, knee translations calculated from stereophotogrammetric data using the proposed compensation method were found to be reliable with respect to the fluoroscopy-based gold standard. The residual mean values of the root mean square error were 2.0, 2.8, and 2.1 mm for anterior/posterior, vertical, and medio/lateral translations, respectively.