Clinical trials with both recombinant and natural alpha and beta interferons have shown that patients may develop neutralizing antibodies to these proteins. Differences in trial design and in the sensitivity of the assays used to measure antibodies have made it difficult to evaluate the factors that influence antibody formation and the effects of these antibodies on clinical results. In several trials, neutralizing antibodies to the recombinant alpha interferons were temporally associated with decreased response to therapy in a few patients, particularly those with B-cell disorders; however, these antibodies had no effect on clinical outcome in other trials. Long periods of treatment and/or higher doses of interferons, both of which contribute to increased cumulative doses of protein, generally are associated with a higher incidence of antibody formation. The source of protein, the route of administration, and the underlying disease also may influence the development of antibodies. Further studies must assess the role of each of these factors carefully to determine which patients are most likely to develop neutralizing antibodies so that clinical effects can be quantitated and appropriate management can be recommended.