The gene SEL1L is involved both in human breast and pancreatic cancer progression. It is located on 14q24.3-31, a region known to be lost in invasive cancer of the esophagus. We aimed to assess whether SEL1L could become a useful biomarker for this cancer. We assessed SEL1L mRNA and protein expression in 35 patients and found it to be weak in low-grade and strong in high-grade dysplasia. Although the majority of cancer patients showed differential expression (mRNA and protein) of SEL1L, in five cases it was completely absent; these patients had the worst outcomes. SEL1L immunoreactivity was negative in normal tissue samples from five patients with mild esophagitis as well as in normal mucosa adjacent to the tumor. We hypothesize that SEL1L could influence those cellular changes that mediate the transition from a normal mucosa to a neoplastic lesion and may help in the identification of those patients at higher risk of developing this cancer. The specific impact of SEL1L in esophageal cancer needs further investigation.