Cordycepin requires the relatively toxic co-drug, deoxycoformycin, for full efficacy as an anticancer agent. We sought to improve cordycepin efficacy using other, less toxic co-drugs.We evaluated the ability of hydroxyurea (HU) to enhance the effects of cordycepin against MOLT-4 leukemia cells with the MTT cell viability assay. We determined the relationship of the combination drug treatment with CalcuSyn statistical analysis program according to the Chou-Talalay method.HU (50 microg/ml) was found to reduce the IC50 of cordycepin from 100 microM to 0.3 microM, a reduction similar to that observed for deoxycoformycin. CalcuSyn analysis of the cordycepin/HU combination revealed the dose effect as synergistic. Further statistical analysis demonstrated a clear synergy between the two drugs at a range of dosages.HU was identified as a promising potential alternative for anti-cancer therapy with cordycepin, thus eliminating the need for the toxic deoxycoformycin.