A polycythaemia vera patient who initially responded to recombinant IFN-alpha 2 (rIFN-alpha 2) treatment developed neutralizing antibodies (NA) against it and lost response. Despite raising the dose, clinical resistance persisted and NA increased when two alternative rIFN-alpha 2 preparations were used. When treatment was switched to lymphoblastoid IFN-alpha (lyIFN-alpha N1), clinical response was restored and maintained. During re-treatment, NA specific for the earlier rIFN-alpha 2 preparations redeveloped and cross-reacted extensively with each other but not with 'whole' lyIFN-alpha N1 and only minimally with the lyIFN-alpha 2 subtype within it. These findings demonstrate the relevance of NA specificities in the re-treatment of antibody-compromised patients.