Serpins are the largest family of protease inhibitors involved in the regulation of many proteolytic processes mediated by serine proteases. Neutrophil granule serine proteases contribute in various ways to immunity by killing microbes and to inflammatory processes through cleavage of soluble proteins, cell surface receptors and tissue matrix proteins. In investigating the functions of nucleocytoplasmic clade B serpins expressed in granulocytes, new functions for neutrophil granule proteases in cellular homeostasis have emerged. Serpinb1 efficiently inhibits neutrophil elastase proteinase-3 and cathepsin G. Deletion of mouse serpinb1a was associated with reduced neutrophil survival in steady state and inflammation. Serpinb1 was found to protect neutrophils from cell death mediated by granule serine protease cathepsin G in a cell-intrinsic manner. While serpinb6 is expressed in neutrophils and also inhibits cathepsin G, the deletion of its mouse homolog serpinb6a was only associated with a slight reduction in neutrophil numbers in the bone marrow. Strikingly, deletion of both serpinb1a and serpinb6a led to a more severe reduction neutrophil numbers and a heightened susceptibility to granule permeabilization-mediated cell death. Our results indicate that inhibition of cathepsin G by intracellular serpins is essential for neutrophil survival.