Barrett's esophagus (BE) is a precancerous condition. However, the mechanisms underlying the transformation from metaplastic to dysplastic to adenocarcinomatous epithelium are still poorly understood. As loss of transforming growth factor-beta growth inhibition is considered a hallmark of several human neoplasms, we evaluated the expression of Ski and SnoN (proteins that antagonize transforming growth factor-beta signaling through physical interaction with Smad complex and by recruiting histone deacetylases), as markers of the transforming growth factor-beta signaling pathway, in BE with and without dysplasia. Biopsy samples from 37 patients (26 men, aged 60 +/- 8 years) with histologically proven BE were evaluated; 10 patients had concomitant low-grade dysplasia, 7 high-grade dysplasia (HGD), and 6 HGD associated with adenocarcinoma. Ski and SnoN expression was assessed immunohistochemically. Neither Ski nor SnoN was expressed in normal esophageal epithelium, but both were strongly expressed in BE tissue, with intense cytoplasmic positivity. Expression of these proteins decreased markedly in dysplastic areas in patients with low-grade dysplasia and was absent in those with HGD or HGD/adenocarcinoma. Ski and SnoN proteins are overexpressed in BE and may be involved in abnormal signaling elicited by transforming growth factor-beta in this epithelium, enhancing the tumorigenesis process. These observations might help to elucidate the molecular mechanisms involved in the BE tumorigenesis process.