Internal fixation with the use of locking plates is the standard surgical treatment for proximal humerus fractures, one of the most common fractures in the elderly. Screw cut-out through weak cancellous bone of the humeral head, which ultimately results in collapse of the fixed fracture, is the leading cause of failure and revision surgery. In an attempt to address this problem, surgeons often attach the plate with as many locking screws as possible into the proximal fragment. It is not thoroughly understood which screws and screw combinations play the most critical roles in fixation stability. This study conducted a detailed finite element analysis to evaluate critical parameters associated with screw cut-out failure. Several clinically relevant screw configurations and fracture gap sizes were modeled. Findings demonstrate that in perfectly reduced fracture cases, variation of the screw configurations had minor influence on mechanical stability of the fixation. The effects of screw configurations became substantial with the existence of a fracture gap. Interestingly, the use of a single anterior calcar screw was as effective as utilizing two screws to support the calcar. On the other hand, the variation in calcar screw configuration had minor influence on the fixation stability when all the proximal screws (A-D level) were filled. This study evaluates different screw configurations to further understand the influence of combined screw configurations and the individual screws on the fixation stability. Findings from this study may help decrease the risk for screw cut-out with proximal humerus varus collapse and the associated economic costs.