Universally expressed CD59 is the sole membrane complement regulatory protein that protects host cells from complement damage by restricting membrane attack complex assembly. The human gene encodes a single CD59, whereas the mouse gene encodes a duplicated CD59, comprising mCd59a and mCd59b, with distinct tissue distribution. Recently, we revealed that Sp1 regulates constitutive CD59 transcription and that canonical nuclear factor kappa light chain enhancer of activated B cells (NF-κB) and cyclic AMP-responsive element-binding protein (CREB) regulate inducible CD59 transcription. However, the mechanisms that underlie mCd59 regulation remain unclear. Here we demonstrate that Sp1 controls broadly distributed mCd59a expression, whereas serum response factor (SRF) and canonical NF-κB regulate selectively expressed mCd59b. Tumor necrosis factor-α in vitro and lipopolysaccharide in vivo remarkably enhance the expression of mCd59b but not mCd59a by activating SRF and NF-κB, thus protecting cells from complement attack. In addition, cAMP analog treatment also dramatically increases mCd59b but not mCd59a expression in a manner independent of CREB, SRF and NF-κB. Therefore, mCd59b but not mCd59a may be the responder to external inflammatory stimuli and may have an important role in complement-mediated mouse models of disease.