Transmitted by ticks, Lyme disease (LD) is the most common vector-borne disease in North America and has experienced an expanded geographical range and increasing number of cases in recent years. No effective prevention is currently available. The causative agent of LD, Borrelia burgdorferi sensu lato ( Bb sl), is a complex containing a variety of species. To escape from killing by complement, one of the mammalian host defense mechanisms, Bb sl produces outer surface proteins that bind to a complement inhibitor, factor H (FH). These FH-binding proteins (i.e., CspA, CspZ, and OspE) evade complement by recruiting FH to the bacterial surface. Here we produced two FH-Fc fusion proteins, which combine human immunoglobulin Fc with the human FH domains that bind to Bb sl FH-binding proteins. We found that FH-Fc constructs kill Bb sl in vitro and prevent colonization and LD manifestations in murine models, correlating with these FH-Fc constructs' ability to bind to CspA, CspZ, and OspE from respective Bb sl species. These results suggest the possibility of using FH-Fc as a prevention against LD.