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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 t 1/2 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 t 1/2 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., (Copyright © 2018 by the American Society of Nephrology.)