Inborn deficiencies of the alternative pathway (AP) of the complement system have been associated with life-threatening infections, mainly by encapsulated bacteria. Complete factor D (FD) deficiencies have been reported in only seven families in the literature. We report two new cases of biochemically and genetically confirmed complete FD deficiency, including the first in a Down syndrome patient. The index cases respectively suffered from severe H. influenza and N. meningitidis infections. Their FD activity was undetectable but was restored by adding recombinant human FD. FD levels were undetectable in the plasma of both patients using ELISA. Genetic analysis of the CFD gene identified a homozygous missense variant p.M40R in one patient, and compound heterozygous variants-a nonsense mutation p.Cys148* and a splice site variant c.212+2T>
G-in the other. Patients with Down syndrome are more susceptible to infections, but this case highlights the importance of investigating the complement system, particularly the AP, even in those with Down syndrome or other secondary immune deficiencies. A familial study should follow if a congenital deficiency is found. The natural history of patients with inherited complete FD deficiency underscores the necessity of preventive measures against encapsulated bacteria for those receiving therapeutic MASP-3 or FD inhibitors.