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Objective: Oncolytic adenovirus, also called conditionally replicating adenovirus (CRAD), has been developed for the treatment of cancer. However, there is a tremendous need to enhance their antitumor efficacy. Here we wish to evaluate whether a strategy that combines the herpes simplex virus-thymidine kinase with oncolytic effects offers a therapeutic advantage.Methods: A novel adenovirus Ad-ETK containing a sequentially positioned promoter of human telomerase reverse transcriptase (hTERT), the coding sequence of E1A gene, an intal ribosome entry site sequence (IRES) and the coding sequence of herpes simplex virus-thymidine kinase (HSV-TK) was constructed. Infection of various cells with Ad-ETK followed by RT-PCR confirmed the expression of E1A and HSV-TK. The oncolytic ability and synergism between oncolytic effects and HSV-TK system was measured. The infection efficiency was determined by flow cytometry.Results: Ad-ETK deliverys E1A and HSV-TK gene, which selectively replicates in hTERT-positive tumor cells, and the progeny virus can reach up to 150 IU/cell. Our in vitro study showed that Ad-ETK plus ganciclovir (GCV) induced an obvious cell death.Conclusion: An oncolytic adenovirus plus the HSV-TK/GCV suicide gene system resulted in a significant improvement in treatment efficacy and it may offer important considerations in the development and preclinical assessments of oncolytic virotherapy.