To formally explore the potential therapeutic effect of histone deacetylase inhibitors (HDACI) and DNA-methyltransferase inhibitors (DNA-MI) on sarcomas, we treated a large sarcoma cell line panel with five different HDACIs in the absence and presence of the DNA-MI decitabine. We observed that the IC(50) value of each HDACI was consistent for all cell lines whereas decitabine as a single agent showed no growth inhibition at standard doses. Combination HDACI/DNA-MI therapy showed a preferential synergism for specific sarcoma cell lines. Subsequently, we identified and validated (in vitro and in vivo) a two-gene set signature (high CUGBP2; low RHOJ) that associated with the synergistic phenotype. We further uncover that the epigenetic synergism leading to specific upregulation of CDKI p21 in specific cell lines is a function of the differences in the degree of baseline chromatin modification. Finally, we show that these chromatin and gene expression patterns are similarly present in the majority of high-grade primary sarcomas. Our results provide the first demonstration of a gene set that can predict responsiveness to HDACI/DNA-MI and links this responsiveness mechanistically to the baseline chromatin structure.