STUDY DESIGN: Biomechanical study. PURPOSE: To quantitatively investigate the effect of screw size on screw fixation in osteoporotic vertebrae with finite element analysis (FEA). OVERVIEW OF LITERATURE: Osteoporosis poses a challenge in spinal instrumentation; however, the selection of screw size is directly related to fixation and is closely dependent on each surgeon's experience and preference. METHODS: Total 1,200 nonlinear FEA with various screw diameters (4.5-7.5 mm) and lengths (30-50 mm) were performed on 25 patients (seven men and 18 women; mean age, 75.2±10.8 years) with osteoporosis. The axial pullout strength, and the vertebral fixation strength of a paired-screw construct against flexion, extension, lateral bending, and axial rotation were examined. Thereafter, we calculated the equivalent stress of the bone-screw interface during nondestructive loading. Then, using diameter parameters (screw diameter or screw fitness in the pedicle [%fill]), and length parameters (screw length or screw depth in the vertebral body [%length]), multiple regression analyses were performed in order to evaluate the factors affecting various fixations. RESULTS: Larger diameter and longer screws significantly increased the pullout strength and vertebral fixation strength; further, they decreased the equivalent stress around the screws. Multiple regression analyses showed that the actual screw diameter and %length were factors that had a stronger effect on the fixation strength than %fill and the actual screw length. Screw diameter had a greater effect on the resistance to screw pullout and flexion and extension loading (β =0.38-0.43, p <0.01); while the %length had a greater effect on resistance to lateral bending and axial rotation loading (β =0.25-0.36, p <0.01) as well as mechanical stress of the bone-screw interface (β =-0.42, p <0.01). CONCLUSIONS: The screw size should be determined based on the biomechanical behavior of the screws, type of mechanical force applied on the corresponding vertebra, and anatomical limitations.