Complement Factor I (CFI) is a trypsin-like serine protease essential for regulating all complement pathways by inactivating C3b and C4b through proteolytic cleavage 1. CFI requires cofactors—factor H and C4BP in fluid phase, or membrane cofactor protein/CD46 and CR1 on cell surfaces—to execute these regulatory functions 2. This cofactor dependency creates a discrimination mechanism: healthy cells with these cofactors allow CFI-mediated C3b degradation, preventing inappropriate complement activation, while apoptotic cells and microbes lacking cofactors undergo complement-mediated opsonization 3. Complete CFI deficiency causes heightened susceptibility to infections, particularly from encapsulated organisms like Neisseria meningitidis, alongside immune dysregulatory manifestations including rheumatologic, neurologic, and renal disorders 4. CFI expression is upregulated by interleukin-6 through increased transcription and mRNA stability, indicating inflammatory regulation of complement control 5. Genetic variations in CFI, particularly the rs10033900 polymorphism, associate with age-related macular degeneration risk, with C-allele carriers showing decreased disease susceptibility 6. Early diagnosis of CFI deficiency and targeted therapies like eculizumab demonstrate clinical benefit 4, establishing CFI as a critical immune checkpoint warranting therapeutic intervention.