Persistent pain is an important cause of patient dissatisfaction after unicompartmental knee replacement (UKR) and has been correlated with localized tibial strain. However, the factors that influence these strains are not well understood. To address this issue, we created finite element models to examine the effect on tibial strain of: (1) muscle forces (estimated using instrumented knee data) acting on attachment sites on the proximal tibia, (2) UKR implantation, (3) loading position, and (4) changes in gait pattern. Muscle forces acting on the tibia had no significant influence on strains within the periprosthetic region, but UKR implantation increased strain by 20%. Strain also significantly increased if the region of load application was moved >3 mm medially. The strain within the periprosthetic region was found to be dependent on gait pattern and was influenced by both medial and lateral loads, with the medial load having a greater effect (regression coefficients: medial = 0.74, lateral = 0.30). These findings suggest that tibial strain is increased after UKR and may be a cause of pain. It may be possible to reduce pain through modification of surgical factors or through altered gait patterns.