A variable pitch locking screw is intended to provide interfragmentary compression combined with fixed angle stability of locking plate constructs. The objective of this study was to compare variable pitch locking screws (3.5-mm KreuLock Ti locking compression screws, Arthrex Inc., Naples, FL) with standard locking screws (from the same manufacturer) in bicortical fixation scenarios in cadaver bone by assessing (1) interfragmentary compression and plate-bone compression and (2) construct biomechanical stability. Nine matched pairs of fresh-frozen cadaveric specimens with an average age of 67.2 years (range, 37-83) were used. Interfragmentary compression and plate-bone compression associated with insertion of single bicortical screws were compared between the variable pitch and standard locking screws at increasing levels of torque. The specimens tested were distal tibiae having a simulated longitudinal fracture. Additionally, fibulae were osteotomized to create a stable longitudinal fracture pattern and were fixed with a 5-screw plate construct with either all variable pitch or all standard locking screws. One of the 5 screws was placed across the osteotomy without lagging. Fibulae were tested cyclically with axial with torsional loading to compare displacements, rotation, and loads at failure or tested in 4-point bending to compare construct stiffness and maximum force to failure. Interfragmentary and plate-bone compression forces in the distal tibia model varied across specimens but were significantly higher with variable pitch locking screws compared with standard locking screws [512 N (SD = 324 N) vs. 79 N (SD = 64 N), P = 0.002, and 242 N (SD = 119 N) vs. 104 N (SD = 123 N), P = 0.028, respectively]. In cyclic loading of fibula constructs, no significant differences were detected in construct axial displacement or angular displacement (P > 0.05). In 4-point bending, no differences were detected in maximum force or bending stiffness (P > 0.05). Variable pitch locking screws produced interfragmentary compression between cortices and plate-bone compression that was greater than that produced by standard locking screws. In a stable bicortical fibula fixation scenario under external loading, the stability of variable pitch locking screw constructs was similar to constructs with standard locking screws.