The long-term therapeutic efficacy of alpha IFN and the influence of preC variants on the type of response were evaluated in 25 patients with chronic hepatitis B, 14 HBeAg and 11 antiHBe positive patients, treated with alpha IFN and monitored for at least four years after discontinuing therapy. In both groups of patients, serum HBV-DNA became frequently undetectable by DNA dot blot during treatment, suggesting that alpha IFN has an antiviral effect both on HBeAg and antiHBe positive chronic carriers. However, long term follow up showed that the loss of viral DNA in antiHBe carriers was only transient, because all responder patients relapsed from 1 to 48 months after IFN withdrawal. In the HBeAg positive carriers, selection for preC mutants was observed at the end of follow up in 2 patients who seroconverted to antiHBe and remained viremic. Both the frequent occurrence of reactivations in antiHBe compared to HBeAg carriers, and the association of IFN therapy with preC mutant virus selection during long term post-treatment follow up observed in this study, indicate that preC variants are more resistant to IFN therapy than preC wild type HBV. Our data suggest therefore, that IFN therapy may be less frequently able to induce a permanent remission in patients infected with preC mutants.