Background C3 glomerulopathy (C3G) is associated with dysregulation of the alternative pathway of complement activation, and treatment options for C3G remain limited. Complement factor H (FH) is a potent regulator of the alternative pathway and might offer a solution, but the mass and complexity of FH makes generation of full-length FH far from trivial. We previously generated a mini-FH construct, with FH short consensus repeats 1-5 linked to repeats 18-20 (FH(1-5^18-20)), that was effective in experimental C3G. However, the serum t1/2 of FH(1-5^18-20) was significantly shorter than that of serum-purified FH.Methods We introduced the oligomerization domain of human FH-related protein 1 (denoted by R1-2) at the carboxy or amino terminus of human FH(1-5^18-20) to generate two homodimeric mini-FH constructs (FH(R1-2^1-5^18-20) and FH(1-5^18-20^R1-2), respectively) in Chinese hamster ovary cells and tested these constructs using binding, fluid-phase, and erythrocyte lysis assays, followed by experiments in FH-deficient Cfh-/- mice.Results FH(R1-2^1-5^18-20) and FH(1-5^18-20^R1-2) homodimerized in solution and displayed avid binding profiles on clustered C3b surfaces, particularly FH(R1-2^1-5^18-20) Each construct was >10-fold more effective than FH at inhibiting cell surface complement activity in vitro and restricted glomerular basement membrane C3 deposition in vivo significantly better than FH or FH(1-5^18-20) FH(1-5^18-20^R1-2) had a C3 breakdown fragment binding profile similar to that of FH, a >5-fold increase in serum t1/2 compared with that of FH(1-5^18-20), and significantly better retention in the kidney than FH or FH(1-5^18-20)Conclusions FH(1-5^18-20^R1-2) may have utility as a treatment option for C3G or other complement-mediated diseases.