Tipifarnib or a tipifarnib derivative is used to treat HDV infection as a monotherapy or in combination with an interferon and/or boosting agent such as a CYP3A4 inhibitor such as ritonavir and cobicistal. This invention arises in part out of the surprising discoveries that not all prenyltransferase inhibitors are efficacious in treating HDV infection and that tipifarnib (Rl 15777) and tipifarnib derivatives such as R208176 can be administered at a dose efficacious in humans. This invention accordingly provides a method of inhibiting HDV replication in a human subject known to be co-infected with HBV and HDV by administering a therapeutically effective dose of tipifarnib, R208176 and other therapeutically effective tipifarnib derivatives and pharmaceutically acceptable salts and other forms.