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Motivation Synergistic drug combinations are a promising approach to achieve a desirable therapeutic effect in complex diseases through the multi-target mechanism. However, in vivo screening of all possible multi-drug combinations remains cost-prohibitive. An effective and robust computational model to predict drug synergy in silico will greatly facilitate this process. Results We developed DIGREM (Drug-Induced Genomic Response models for identification of Effective Multi-drug combinations), an online tool kit that can effectively predict drug synergy. DIGREM integrates DIGRE, IUPUI_CCBB, gene set-based and correlation-based models for users to predict synergistic drug combinations with dose–response information and drug-treated gene expression profiles. Availability and implementation http://lce.biohpc.swmed.edu/drugcombination Supplementary information Supplementary data are available at Bioinformatics online. [ABSTRACT FROM AUTHOR]