HDAC genes are thought to be involved in gene expression through the regulation of chromatin structure, alterations of which may cause abnormal gene silencing in cancers. To clarify the possible role of HDAC genes during tumor development and progression, we studied their expression and influence on clinical features. Expression levels of HDAC class I and class II genes in cancer tissues resected from 72 patients with NSCLC were measured with real‐time RT‐PCR. Their association with clinicopathologic features was statistically investigated. Reduced expression of each class II HDAC gene was significantly associated with poor prognosis and an independent predictor of poor prognosis. Of all the genes, HDAC10 was the strongest predictor of poor prognosis. Hierarchical clustering analysis showed that lung cancer tissues could be divided into 3 groups based on the expression level of class I and class II HDAC genes. The group with reduced expression of class II HDACs showed poor prognosis. These results suggest that class II HDACs may repress critical genes and that low expression of these genes may play a role in lung cancer progression. Results of clustering analyses imply that class II HDAC genes may be regulated by a similar mechanism and deregulated during cancer development. © 2004 Wiley‐Liss, Inc.