The frictional performances of surgical sutures have been found to play a vital role in their functionality. The purpose of this paper is to understand the frictional performance of multifilament surgical sutures interacting with skin substitute, by means of a penetration friction apparatus (PFA). The influence of the size of the surgical suture was investigated. The relationship between the friction force and normal force was considered, in order to evaluate the friction performance of a surgical suture penetrating a skin substitute. The friction force was measured by PFA. The normal force applied to the surgical suture was estimated based on a Hertzian contact model, a finite element model (FEM), and a uniaxial deformation model (UDM). The results indicated that the penetration friction force increased as the size of the multifilament surgical suture increased. In addition, when the normal force was predicted by UDM, it was found that the ratio between the friction force and normal force decreased as the normal force increased. A comparison of the results suggested that the UDM was appropriate in predicting the frictional behavior of surgical suturing.