Background: The fracture obliquity of supination-external rotation injury of the fibula is often amenable to lag screw insertion.The purpose of the study was to determine whether biomechanical differences exist between lag screws inserted from an anterior to posterior direction and from a posterior to anterior direction and the thickness of the anterior and posterior fibular cortices were correlated with biomechanical testing. Methods: Ten cadaver fibulae were harvested and submitted to material testing following 3.5-mm cortical screw insertion from either an anterior to posterior direction or a posterior to anterior direction. Screw torsional insertion strength and axial pullout strength were measured. Computed tomography images of 40 consecutive patients undergoing preoperative planning for fractures excluding the fibula were examined to define fibular cortical thickness and correlate anatomic findings with the biomechanical testing. Results: The axial pullout strength of lag screws inserted from posterior to anterior was significantly greater than that of lag screws inserted from anterior to posterior (p < 0.05). Screw insertion torque measurements demonstrated a similar trend although the data did not reach statistical significance (p = 0.056). The anterior cortex of the distal fibula exhibited a radiographically greater thickness than that of the posterior cortex at the same level (p < 0.001). Conclusions For oblique fractures of the distal fibula, posterior to anterior lag screw insertion exhibited improved biomechanical properties when compared with a similar screw inserted from anterior to posterior. These results correlated with the thicker cortical bone present along the anterior fibula.