As a solution to restore knee function and reduce pain, the demand for Total Knee Arthroplasty (TKA) has dramatically increased in recent decades. The high rates of dissatisfaction and revision makes it crucially important to understand the relationships between surgical factors and post-surgery knee performance. Tibial implant alignment in the sagittal plane (i.e., posterior tibia slope, PTS) is thought to play a key role in quadriceps muscle forces and contact conditions of the joint, but the underlying mechanisms and potential consequences are poorly understood. To address this biomechanical challenge, we developed a subject-specific musculoskeletal model based on the bone anatomy and precise implantation data provided within the CAMS-Knee datasets. Using the novel COMAK algorithm that concurrently optimizes joint kinematics, together with contact mechanics, and muscle and ligament forces, enabled highly accurate estimations of the knee joint biomechanics (RMSE <0.16 BW of joint contact force) throughout level walking and squatting. Once confirmed for accuracy, this baseline modelling framework was then used to systematically explore the influence of PTS on knee joint biomechanics. Our results indicate that PTS can greatly influence tibio-femoral translations (mainly in the anterior-posterior direction), while also suggesting an elevated risk of patellar mal-tracking and instability. Importantly, however, an increased PTS was found to reduce the maximum tibio-femoral contact force and improve efficiency of the quadriceps muscles, while also reducing the patellofemoral contact force (by approximately 1.5% for each additional degree of PTS during walking). This study presents valuable findings regarding the impact of PTS variations on the biomechanics of the TKA joint and thereby provides potential guidance for surgically optimizing implant alignment in the sagittal plane, tailored to the implant design and the individual deficits of each patient.