Pulmonary macrophages are one of the sources of various antioxidant and detoxification enzymes for which NF-E2-related factor 2 (Nrf2) is a key transcriptional factor. Although Nrf2 deficiency reportedly induces severe emphysema in smoking mice, no reports have studied Nrf2 regulation in chronic obstructive pulmonary disease (COPD). In this study, Nrf2 activation in response to cigarette smoke (CS) was evaluated in human alveolar macrophages, and age-related differences in CS-induced Nrf2 regulation in mouse alveolar macrophages were determined. Furthermore, Nrf2 mRNA levels in human macrophages harvested by bronchoalveolar lavage (BAL) or laser capture microdissection (LCM) were measured. CS induced nuclear Nrf2 accumulation and upregulation of Nrf2 target genes without substantial changes in Nrf2 mRNA levels in human alveolar macrophages. In humans, the Nrf2 mRNA level in lavaged macrophages of young subjects (n=14) was independent of smoking status; however, the Nrf2 mRNA level was downregulated in the lavaged macrophages of older current smokers (n=14) compared to older nonsmokers (n=9) (p<0.001). Among older subjects, the macrophage Nrf2 mRNA level was inversely correlated with oxidized glutathione and carbonylated albumin levels in BAL fluid. In mice, aging suppressed the CS-induced upregulation of Nrf2 target genes, as well as Nrf2, in alveolar macrophages. Furthermore, the Nrf2 mRNA level was decreased in LCM-retrieved macrophages obtained from subjects with COPD (n=10) compared to control subjects (n=10) (p=0.001). In conclusion, CS induces Nrf2 activation in macrophages, and Nrf2 expression is decreased in the macrophages of older current smokers and COPD patients.