Provided is a fusion protein comprising, at its carboxy terminal of human erythropoietin (EPO), a mutant having one to four amino acid substitutions in the carboxy terminal peptide (CTP) fragment of a human chorionic gonadotropin (HCG) .beta. subunit, for increasing an in vivo half-life activity of EPO. The in vivo half-life can be greatly elongated while retaining the intrinsic activity of the EPO, without increasing the sugar chain content.