OBJECTIVE In the management of isthmic spondylolisthesis, the pedicle screw system is widely accepted surgical strategy; however, there are few reports on the biomechanical behavior of pedicle screws in spondylolytic vertebrae. The purpose of the present study was to compare fixation strength between pedicle screws inserted through the traditional trajectory (TT) and those inserted through a cortical bone trajectory (CBT) in spondylolytic vertebrae by computational simulation. METHODS Finite element models of spondylolytic and normal vertebrae were created from CT scans of 17 patients with adult isthmic spondylolisthesis (mean age 54.6 years, 10 men and 7 women). Each vertebral model was implanted with pedicle screws using TT and CBT techniques and compared between two groups. First, fixation strength of a single screw was evaluated by measuring axial pullout strength. Next, vertebral fixation strength of a paired-screw construct was examined by applying forces simulating flexion, extension, lateral bending, and axial rotation to vertebrae. RESULTS Fixation strengths of TT screws showed a nonsignificant difference between the spondylolytic and the normal vertebrae (p = 0.31-0.81). Fixation strength of CBT screws in the spondylolytic vertebrae demonstrated a statistically significant decrease in pullout strength (21.4%, p < 0.01), flexion (44.1%, p < 0.01), extension (40.9%, p < 0.01), lateral bending (38.3%, p < 0.01), and axial rotation (28.1%, p < 0.05) compared with those in the normal vertebrae. In the spondylolytic vertebrae, no statistically significant difference was observed for pullout strength between TT and CBT (p = 0.90); however, the CBT construct showed lower vertebral fixation strength in flexion (39.0%, p < 0.01), extension (35.6%, p < 0.01), lateral bending (50.7%, p < 0.01), and axial rotation (59.3%, p < 0.01) compared with the TT construct. CONCLUSIONS CBT screws are less optimal for stabilizing the spondylolytic vertebra due to their lower fixation strength compared with TT screws.