The human neutrophil spontaneously undergoes apoptosis, but this type of cell death can be delayed or accelerated by a wide variety of agents. There are wide discrepancies in the literature regarding the expression of the Bcl-2 family of proteins in human neutrophils. Here, we show that Al, Mcl-1, Bel-X-L, and Bad are major transcripts in human neutrophils and that levels of these transcripts are cytokine regulated. However, no Bel-XL protein was detected in Western blots. Protein levels for the proapoptotic proteins Bad, Bax, Bali., and Bik. remained constant during culture, despite changes in the levels of mRNA for these gene products. These proapoptotic proteins were extremely stable, having very long half-lives. In contrast, Al and Mcl-1 transcripts were extremely unstable (with similar to3-h half-lives), and Mcl-1 protein was also subject to rapid turnover. These results indicate that neutrophil survival is regulated by the inducible expression of the short-lived Mcl-1 and possibly the Al gene products. In the absence of their continued expression, these prosurvival gene products are rapidly turned over, and then the activity of the stable death proteins predominates and promotes apoptosis.