Implants can induce a foreign body reaction that leads to chronic inflammation and fibrosis in the surrounding tissue. Macrophages help detect the foreign material, play a role in the inflammatory response, and may promote fibrosis instead of the desired tissue regeneration around implants. Implant surface properties impact macrophage responses by changing the nature of the adsorbed protein layer, but conflicting studies highlight the complexity of this relationship. In this study, the effect of surface chemistry on macrophage behavior was investigated with poly(styrene) surfaces containing common functional groups at similar surface densities. The protein layer was characterized to identify the proteins that adsorbed on the surfaces from the medium and the proteins secreted onto the surfaces by adherent macrophages. Of the surface chemistries studied, carboxylic acid (COOH) groups promoted anti-inflammatory responses from unstimulated macrophages and did not exacerbate inflammation upon stimulation. These surfaces also enhanced the adsorption of proteins involved in integrin signaling and promoted the secretion of proteins related to angiogenesis, integrin signaling, and cytokine signaling, which have been previously associated with improved biomaterial integration. Therefore, this study suggests that surface modification with COOH groups may help improve the integration of implants in the body by enhancing anti-inflammatory macrophage responses through altered protein adsorption.