The present invention relates generally to the generation and characterization of neutralizing anti-IFN-.alpha. monoclonal antibodies with broad reactivity against various IFN-.alpha. subtypes. The invention further relates to the use of such anti-IFN-.alpha. antibodies in the diagnosis and treatment of disorders associated with increased expression of IFN-.alpha., in particular, autoimmune disorders such as insulin-dependent diabetes mellitus (IDDM) and systemic lupus erythematosus (SLE).