IFN-α has been shown to elicit antitumor activity in carcinoid tumors. In the present study the effects of IFN-α on the protein expression involved in the IFN-α signaling, which were recognized as signal transducer and activators of transcription (Stats), were investigated. Archive specimens from 45 carcinoid patients, 33 before IFN-α and 45 during treatment, were studied. The tissues were immunostained for protein expression by using monoclonal anti-Stat1 and anti-Stat2 antibodies. Results showed that Stat1 and Stat2 immunostaining were significantly increased during IFN-α treatment. Stats scores were significantly increased only in patients with objective response as well as those with stable disease but not in those with progressive disease. The induction of Stats correlated with the survival rates of the patients. In addition, both Stat scores significantly correlated with the p68 protein expression. In a carcinoid tumor cell line, Bon1, IFN-α dose-dependently increased the Stat expression. Analysis of cell fractions showed that IFN-α increased Stat protein both in cytoplasm and nucleoplasm of the cells. Furthermore, IFN-α enhanced tyrosine phosphorylation of Stat1 and Stat2. Thus, the antitumor effect, in vivo and in vitro, in IFN-α-treated carcinoid tumors seems to be mediated via upregulation of Stat proteins and enhancement of phosphorylation of these proteins.