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 mice exposed to cigarette smoke (CS), no reports have studied Nrf2 regulation in chronic obstructive pulmonary disease (COPD). In this study, Nrf2 activation in response to 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 or laser capture microdissection were measured. CS induced nuclear Nrf2 accumulation and up-regulation 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 down-regulated in the lavaged macrophages of older current smokers (n = 14) compared with 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 bronchoalveolar lavage fluid. In mice, aging suppressed the CS-induced up-regulation of Nrf2 target genes, as well as Nrf2, in alveolar macrophages. Furthermore, the Nrf2 mRNA level was decreased in laser capture microdissection-retrieved macrophages obtained from subjects with COPD (n = 10) compared with 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 patients with COPD.