Protease resistant modified interferon-beta polypeptides, and pharmaceutical compositions containing such modified interferon-beta polypeptides are provided. The modified interferon-beta polypeptides contain amino acid substitutions that confer increased resistance to proteolysis over unmodified IFN beta cytokine molecules. The present invention provides for pharmaceutical formulations suitable for oral, nasal and pulmonary administration, and the use of such formulations in the treatment of disease.