Recently Smac/DIABLO (second mitochondria-derived activator of caspase) has been identified as a proapoptotic protein that inhibits IAPs (inhibitors of apoptosis proteins). Smac is expressed ubiquitously in many organs, including the lung. Here we evaluated the expression of Smac mRNA with real-time reverse-transcription PCR in 88 primary lung cancers and matched normal tissues. Smac mRNA expression in tumor tissues was significantly lower than that in normal tissues (p<0.0001). In squamous cell carcinomas, Smac mRNA expression was significantly lower than that in adenocarcinomas (p=0.0072). Smac mRNA expression in T2-T4 tumors was significantly lower than that in T1 tumors (p=0.0006). The expression of Smac in the tumors of smokers was lower than that in the tumors of non-smokers (p=0.0011). The prognosis of patients with a tumor exhibiting a low expression of Smac mRNA was worse than that in those with a tumor exhibiting high Smac mRNA expression (log-rank test, p=0.047). These results indicate that Smac expression may play a role in the carcinogenesis, progression, and prognosis of primary lung cancer.