Esophageal squamous cell carcinoma (ESCC) in the Indian population is associated with poor nutritional status, low socioeconomic conditions, bidi smoking and consumption of smokeless tobacco products, besides alcohol drinking and cigarette smoking. To determine the impact of these risk factors on molecular pathogenesis of ESCC, we determined global gene expression profiles of 7 paired samples of ESCC and histologically confirmed nonmalignant esophageal tissues using 19.1K cDNA microarrays. The most salient finding was identification of 19 differentially expressed genes encoding zinc binding or modulating proteins associated with transcriptional regulation, ubiquitin-protein degradation and maintenance of zinc homeostasis. Validation of differential expression of a subset of genes by real-time quantitative RT-PCR (real-time QRT-PCR) in clinical specimens of ESCC, esophageal dysplasia and histologically nonmalignant esophageal tissues and immunohistochemical analysis using tissue microarrays confirmed the microarray data and demonstrated upregulation of zinc finger proteins, cellular modulator of immune recognition (c-MIR), snail homolog 2 (SLUG), zinc transporter, ZnT7 and downregulation of zinc metabolizing protein, metallothionein MT1G. We also observed upregulation of mitogen activated protein kinase kinase kinase 3 (MAP3K3/MEKK3), a kinase anchor protein 13 (AKAP13) and transglutaminase2 (TG2). Interestingly, we found upregulation of ZnT7 transcripts in ESCC cells (TE13) grown in zinc deficient condition. In conclusion, our data suggest deregulation of genes associated with zinc homeostasis in ESCC.