Global histone modification patterns are presumed to establish epigenetic patterns of gene expression and determine the biology of the cell. In the present study, the global modification status of histone H3 and H4 was evaluated in 408 non-small cell lung cancer (NSCLC) tissues by immunostaining. NSCLC showed variable staining scores for each antibody. Clinicopathological analyses demonstrated a positive correlation between weak nuclear staining for H3K9Ac (P < 0.001), H3K9TriMe (P= 0.001), H4K16Ac (P < 0.001) and tumor recurrence except H4K20 TriMe (P= 0.201). Staining scores of four different antibodies were not correlated with other clinicopathologic variables. Patients were further clustered according to histone modification patterns: acetylation dominant, methylation dominant, co-dominant and modification-negative. The acetylation-dominant group (P= 0.009) and co-dominant group exhibited less frequent lymph node metastasis (P= 0.050), recurrence (P= 0.002) and distant metastasis (P= 0.010). The acetylation-dominant group showed better prognosis in survival analysis (P < 0.001, log-rank), whereas methylation-dominant and modification-negative status was associated with poor prognosis. In conclusion, our data suggest that global histone H3 and H4 modification patterns are potential markers of tumor recurrence and disease-free survival in NSCLC patients.