Abstract Staphylococcus aureus is a significant human pathogen that causes a multitude of superficial and invasive infections worldwide. As antibiotic resistance is increasing, novel therapies are in dire need. As a master of immune evasion, S. aureus produces several virulence factors to persist in the host. A primary target of staphylococcal immune evasion is the Complement system, a component of innate immunity central to controlling bacterial infections. We have previously shown that S. aureus binds Complement regulator Factor H (FH) via surface protein SdrE to inhibit Complement. To address the need for novel therapeutics and take advantage of the SdrE:FH interaction, we tested the binding and downstream effect of a fusion protein comprised of the SdrE-interacting domain of FH coupled with IgG1 Fc using a S. aureus clinical isolate known to bind FH. S. aureus bound significantly more FH-Fc than Fc-control proteins indicating a greater affinity for SdrE compared to S. aureus Fc-binding proteins Protein A and Sbi. In the presence of normal human serum, FH-Fc competitively bound to S. aureus and reduced S. aureus recruitment of serum FH compared to Fc-control. When examining the effect of FH-Fc on complement-mediated opsonization of S. aureus, treatment with FH-Fc resulted in a slight increase in C3-fragment deposition and a significant increase in C5a generation compared to control. This may be attributed to the cumulative effect of serum FH displacement plus a boost in classical pathway activation via additional Fc presence afforded by SdrE:FH-Fc binding. Taken together, these data support FH-Fc as a potential anti-staphylococcal therapeutic. Future studies will explore how FH-Fc affects S. aureus survival when challenged with phagocytes.