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Component alignment in total knee arthroplasty is a determining factor for implant longevity. Mechanical alignment, which provides balanced load transfer, is the most common alignment strategy. However, a retrospective review found that varus alignment, which could lead to unbalanced loading, can happen in up to 18% of tibial baseplates. This may be particularly burdensome for cementless tibial baseplates, which require low bone-implant micromotion and avoidance of bone overload to obtain bone ingrowth. Our aim was to assess the effect of varus alignment on the bone-implant interaction of cementless baseplates. We virtually implanted 11 patients with knee OA with a modern cementless tibial baseplate in mechanical alignment and in 2° of tibial varus alignment. We performed finite element simulations throughout gait, with loading conditions derived from literature. Throughout the stance phase, varus alignment had greater micromotion and percentage of bone volume at risk of failure than mechanical alignment. At mid-stance, when the most critical conditions occurred, the average increase in peak micromotion and amount of bone at risk of failure due to varus alignment were 79% and 59%, respectively. Varus alignment also resulted in the decrease of the surface area with micromotion compatible with bone ingrowth. However, for both alignments, this surface area was larger than the average area of ingrowth reported for well-fixed implants retrieved post-mortem. Our findings suggest that small varus deviations from mechanical alignment can adversely impact the biomechanics of the bone-implant interaction for cementless tibial baseplates during gait; however, the clinical implications of such changes remain unclear.