Heme oxygenase-1 (HO-1) is induced by a variety of stress stimuli and by many antitumor agents. We investigated involvement of HO-1 in chemoresistance of cisplatin in human lung epithelial adenocarcinoma cell line, A549, which constitutively expressed HO-1. We found that treatment with cisplatin further augmented HO-1 expression, which was associated with activation of the epidermal growth factor receptor (EGFR) mediated signaling pathway and subsequent nuclear translocation of NF-kappaB. In concordance with the findings, treatment with EGFR-selective tyrosine kinase inhibitor (AG1478) or an Akt inhibitor, which interfere with the post-EGFR signaling pathway, suppressed cisplatin induced HO-1 expression. While either AG1478 or HO-1 siRNA alone did not alter cell viability of A549 cells, both agents significantly augmented cytotoxicity of cisplatin. The similar data also found in large cell carcinoma cell line, H460. Collectively, the results indicate that resistance to cisplatin in A549 cells is associated with HO-1 through EGFR mediated signaling pathway including activation of the PI3k/Akt and NF-kappaB systems. Our data also suggest that the chemosensitivity of A549 cells to cisplatin is restored by EGFR-selective tyrosine kinase inhibitor and an Akt inhibitor.