There is a need to better understand the effects of intervertebral spacer material and design on the stress distribution in vertebral bodies and endplates to help reduce complications such as subsidence and improve outcomes following lumbar interbody fusion. The main objective of this study was to investigate the effects of spacer material on the stress and strain in the lumbar spine after interbody fusion with posterior instrumentation. A standard spacer was also compared with a custom-fit spacer, which conformed to the vertebral endplates, to determine if a custom fit would reduce stress on the endplates. A finite element (FE) model of the L4–L5 motion segment was developed from computed tomography (CT) images of a cadaveric lumbar spine. An interbody spacer, pedicle screws, and posterior rods were incorporated into the image-based model. The model was loaded in axial compression, and strain and stress were determined in the vertebra, spacer, and rods. Polyetheretherketone (PEEK), titanium, poly(para-phenylene) (PPP), and porous PPP (70% by volume) were used as the spacer material to quantify the effects on stress and strain in the system. Experimental testing of a cadaveric specimen was used to validate the model's results. There were no large differences in stress levels (<3%) at the bone–spacer interfaces and the rods when PEEK was used instead of titanium. Use of the porous PPP spacer produced an 8–15% decrease of stress at the bone–spacer interfaces and posterior rods. The custom-shaped spacer significantly decreased (>37%) the stress at the bone–spacer interfaces for all materials tested. A 28% decrease in stress was found in the posterior rods with the custom spacer. Of all the spacer materials tested with the custom spacer design, 70% porous PPP resulted in the lowest stress at the bone–spacer interfaces. The results show the potential for more compliant materials to reduce stress on the vertebral endplates postsurgery. The custom spacer provided a greater contact area between the spacer and bone, which distributed the stress more evenly, highlighting a possible strategy to decrease the risk of subsidence.