Objective: Synergistic drug combinations are promising therapies for cancer treatment. However, effective prediction of synergistic drug combinations is quite challenging as mechanisms of drug synergism are still unclear. Various features such as drug response, and target networks may contribute to prediction of synergistic drug combinations. In this study, we aimed to construct a computational model to predict synergistic drug combinations. Methods: We designed drug physicochemical features and network features, including drug chemical structure similarity, target distance in protein-protein network and targeted pathway similarity. At the same time, we designed fifteen pharmacogenomics features using drug treated gene expression profiles based on the background of cancer-related biology network. Based on these eighteen features, we built a prediction model for Synergistic Drug combination using Random forest algorithm (SyDRa). Results: Our model achieved a quite good performance with AUC value of 0.89 and Out-of-bag estimate error rate of 0.15 in training dataset. Using the random anti-cancer drug combinations which have transcriptional profile data in the Connectivity Map dataset as the testing dataset, we identified 28 potentially synergistic drug combinations, three out of which had been reported to be effective drug combinations by literatures. Conclusions: We studied eighteen features for drug combinations and built a computational model using random forest algorithm. The model was evaluated using an independent test dataset. Our model provides an efficient strategy to identify potentially synergistic drug combinations for cancer and may help reduce the search space for high-throughput synergistic drug combinations screening. (C) 2017 Elsevier B.V. All rights reserved.