M-CSF-induced monocyte-derived macrophages (M-M) required continuous presence of M-CSF for their survival and depletion of M-CSF from the culture induced apoptosis, while human alveolar macrophages (A-M) and GM-CSF-induced monocyte-derived macrophages (GM-M) survived even in the absence of CSF. The expression of Bcl-2 was higher in M-M, and M-CSF withdrawal down-regulated the expression. The expressesion of Bcl-xL was higher in A-M and GM-M, and the expression was CSF-independent. The expression of Mcl-1 and BAX were not different between M-M and GM-M, and were CSF-independent. Down-regulation of the expression of bcl-2 and bcl-xL by RNAi showed the important role of Bcl-2 and Bcl-xL in the survival of M-M and GM-M, respectively. Human erythrocyte catalase (HEC) and conditioned medium (CM) obtained from GM-M or A-M cultured in the absence of GM-CSF prevented the M-M from apoptosis and restored the expression of bcl-2. The activity of the CM was abrogated by pretreatment with anti-HEC antibody. Anti-HEC antibody also induced the apoptosis of M-M cultured in the presence of M-CSF and GM-M and A-M cultured in the presence or absence of GM-CSF, and down-regulated the expression of Bcl-2 and Bcl-xL in these Ms. GM-M and A-M but not M-M can produce both extracellular catalase and cell associated catalase in a CSF-independent manner. Intracellular GSH levels were kept equivalent in these Ms both in the presence or absence of CSF. These results indicate a critical role of extracellular catalase in the survival of human macrophages via regulation of the expression of Bcl-2 family genes. (248 words)