Abstract Background As a major cause of a myriad of superficial and invasive infections worldwide, Staphylococcus aureus is a master of immune evasion, with the complement system being a primary target. Previously, we have shown that S. aureus surface protein SdrE binds the regulator Factor H (FH) to inhibit complement. Taking advantage of this interaction, we tested the effect of a fusion protein comprised of FH(18–20) fused to an IgG Fc on complement-mediated opsonophagocytosis and killing of methicillin resistant S. aureus. Methods Fusions were produced via the ΔXT/FT Nicotiana benthamiana plant expression system. Binding dynamics were examined via immunoblotting, fluorescence and ELISA. The effect of fusions on complement activation was determined by examining C3-fragment opsonization of S. aureus (total C3, C3b, iC3b) and subsequent C5a generation. The effect of fusions on S. aureus survival was assessed using an opsonphagocytosis assay with human polymorphonuclear cells. Results S. aureus bound significantly more FH-Fc compared to Fc-controls, and competed with serum FH for S. aureus binding. FH-Fc outperformed a complement inactive fusion variant in C3-fragment deposition and C5a generation, signifying an active role for the Fc region of FH-Fc. For 75% (3/4) of clinical isolates tested, FH-Fc significantly reduced S. aureus survival. Clinical isolates were all sdrE positive, sequence type 8, SCCmec IVa and Panton-Valentine Leukocidin (pvl) positive). Conclusion FH-Fc competitively inhibited serum FH from S. aureus binding and increased complement-mediated opsonophagocytosis and killing of CA-MRSA. Future studies will focus on enhancing the efficacy of FH-Fc fusion molecules as potential anti-staphylococcal therapeutics. Supported by a grant from the US Department of Defense, USAMRDC (W81XWH-19-1-0119).