Many studies have demonstrated the overexpression and amplification of the miR-17-92 cluster in malignant human cancers, including B-cell lymphomas and lung cancers. The purpose of this study was to investigate for the first time, the expression of the miR-17-92 cluster in esophageal squamous cell carcinoma (ESCC). The miR-17-92 cluster was found to be overexpressed in 21 out of 28 (75%) esophageal cancer samples. It was also found that overexpression of the miR-17-92 cluster could promote cellular growth in vivo and in vitro. Furthermore, inhibition of miR-19a by antisense oligonucleotides (ONs) induced apoptosis, while antisense ONs against miR-17-5p, miR-18a, miR-20a and miR-92-1 did not exhibit such an effect. In addition, it was found that antagomir-19a treatment could impair tumor growth in vivo. Using Human Apoptosis RT2 Profiler PCR Array 384HT, we found that tumor necrosis factor-α (TNF-α) was up-regulated 12-fold in cells transfected with miR-19a antisense ONs compared to the cells treated with the control scramble ONs. MiR-19a was predicted to target the 3' untranslated region of TNF-α mRNA, and this was confirmed by luciferase reporter assay. Taken together, we conclude that the miR-17-92 cluster is overexpressed in ESCC and that TNF-α is a novel target of miR-19a.