Custom-made knee prostheses have been widely used to reconstruct the function of the lower limb in bone tumor resections. A custom-made tumor knee prosthesis was retrieved on account of prosthesis loosening post-surgery. Misalignment between the anatomical axis of the femur and the axis of the femoral stem as well as the material loss at the posterior region of the tibial plateau were considered to be the primary causes of the failure. Based on this hypothesis, finite element analysis was performed to investigate the contact mechanics of the prosthesis while implanted in vivo. The maximum deformation at the femur was 0.59 mm and 1.17 mm when the misalignment angle was 3˚ and 6˚, respectively. Besides, the maximum contact pressure at the tibial plateau was 44.88 MPa at an extremely high flexion of angle 135˚ during squatting or kneeling. Uneven stress distribution at the femur, which came from the misalignment, was the main cause of loosening, which was aggravated indirectly with the material loss at the posterior region of the tibial plateau. Optimized prosthesis design and appropriate selection, with accurate surgical positioning and targeted rehabilitation training programme are important considerations for prolonging life-span of prostheses in vivo.