Among the transcription factors that direct proliferation, differentiation, and death of cells, several Krüppel-like zinc finger molecules such as GLI1 and ZNF147 can become oncogenic when the genes encoding them are overexpressed by the DNA amplification mechanism. Here, we report the discovery of a novel member of this class, ZASC1, from a recently reported critical region of 3q26 amplification frequently observed in various squamous cell carcinomas, including esophageal squamous cell carcinomas (ESCs). The deduced 485-amino acid protein product of ZASC1 contained a putative nuclear localization signal; the exogenously transfected ZASC1 was translocated into cell nuclei. ZASC1 was frequently coamplified and subsequently overexpressed with PIK3CA in our panel of ESC cell lines and primary tumors. In patients with ESC, a higher mRNA expression level of ZASC1 appeared to be associated with shorter overall survival, and a multivariate analysis demonstrated that ZASC1 mRNA expression was an independent prognosticator. In addition, exogenous expression of ZASC1 promoted the growth of ESC cells, whereas down-regulation of ZASC1 expression by means of an antisense oligonucleotide suppressed the growth of ESC cells. Taken together, our results suggest that ZASC1 might be involved in the pathogenesis of ESC as one of the targets for 3q26 amplification, alone or in concert with other targets.