Retinoids such as all trans-retinoic acid (ATRA) have been used as chemopreventive agents for a number of premalignant conditions. To explore a potential role for retinoids as chemopreventive agents for Barrett's esophagus, we studied ATRA's effects on apoptosis in a non-neoplastic, telomerase-immortalized, metaplastic, Barrett's cell line. We treated the Barrett's cells with ATRA in the presence and absence of inhibitors to p53 (pSRZ-siRNA-p53), p38 (SB-203580 and p38 siRNA), and the caspase cascade (z-Val-Ala-Asp-fluoromethyl ketone). We determined the effects of ATRA and the various inhibitors on apoptosis using cell morphology, TUNEL staining, cleaved caspase-3 immunofluoresence, and Annexin V staining. We also determined how ATRA in the presence and absence of the inhibitors affected apoptosis following low dose UV-B irradiation. ATRA induced apoptosis and increased the expression of p53 protein in a dose-dependent fashion. The apoptotic effect of ATRA was abolished by treatment with inhibitors of both p38 and caspase, but not by p53 RNAi. Inhibition of p38 also prevented expression of cleaved caspase-3, suggesting that ATRA activates p38 upstream of the caspase cascade. We found that ATRA sensitized immortalized Barrett's cells to apoptosis induced by low dose UV-B irradiation via a similar mechanism. ATRA induces apoptosis in Barrett's epithelial cells and sensitizes them to apoptosis induced by UV-B irradiation via activation of p38 and the caspase cascade, but not through p53. This study elucidates molecular pathways whereby retinoid treatment might prevent carcinogenesis in Barrett's metaplasia and suggests a potential role for the use of safer retinoids for chemoprevention in Barrett's esophagus.