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Paroxysmal nocturnal hemoglobinuria (PNH) patients are susceptible to complement-mediated intravascular hemolysis and thrombosis. Factor H (FH) is the main regulator of the complement alternative pathway, protecting cells from unwanted complement-mediated damage. Although FH is not a glycosylphosphatidylinositol-linked molecule, it may play a role in PNH. We sought to determine if rare germline variants in CFH affect the PNH course, screening 84 PNH patients treated with eculizumab for rare variants in CFH, CFI and C3 genes. We compared the allele frequencies with populational data and a geographically-matched control group, looking for an association between the variants' presence and treatment response (transfusion independence by six months). Sixteen patients presented rare variants, nine in CFH (10.7%). Germline CFH variants were more frequent among PNH patients than in controls (p=0.02) or public data (p<0.001) and were more likely to be transfusion-dependent at six months after eculizumab initiation (p=0.015). With a median follow-up of 5.8 years, 8/9 CFH-variant patients received transfusions, and two developed thromboses. No CFH-variant patient had severe aplastic anemia from eculizumab initiation until six months. We show for the first time that rare CFH variants are over-represented among PNH patients and that germline genetic background may affect the response to eculizumab.