Inhibition of histone deacetylases (HDACs) is a promising new approach to the treatment of lung cancer therapy. The relation between HDAC3 expression and the clinicopathological characteristics of lung cancer is not well understood, however. We therefore addressed this issue in patients with adenocarcinoma of the lung. We used semi-quantitative real-time reverse transcription polymerase chain reaction and immunohistochemical analysis to assess expression of HDAC3 in tumor samples from 94 patients with adenocarcinoma of the lung. We then correlated levels of HDAC3 expression with known clinicopathological factors. The 5-year disease-free survival (5-DFS) rate among patients expressing high levels of HDAC3 was significantly poorer than among those expressing lower levels (P = 0.005; log-rank test). Multivariate Cox proportional hazard analyses revealed male (hazard ratio, 3.88; 95% CI, 1.70-9.39; P = 0.001), nodal metastasis N1 (hazard ratio, 6.39; 95% CI, 1.54-22.7; P = 0.013), N2 (hazard ratio, 6.36; 95% CI, 1.55-33.6; P = 0.009), and HDAC3 (hazard ratio, 3.06; 95% CI, 1.07-7.55; P = 0.037) to be independent factors affecting the 5-DFS rate. Strong tumoral expression of HDAC3 is an independent predictor of a poor prognosis in patients with adenocarcinoma of the lung.