Background: We describe a patient with generalized verrucosis secondary to human papillomavirus (HPV) type 2 infection and a primary immunodeficiency and cyclic neutropenia. Treatment which was well tolerated, included granulocyte-macrophage colony-stimulating factor and interferon gamma (INF- γ). In vitro assays to assess responses of T lymphocytes to mitogens (ie, proliferation assay and IFN-γ enzyme-linked immunosorbent assay) were performed. In situ hybridization and polymerase chain reaction were used to detect HVP DNA in skin biopsy specimens. Observations: The T lymphocytes of the patient showed a significant (P<.05, unpaired Student t test) defect in IFN-γ production (the basis for initiating IFN-γ therapy). The response to immunotherapy was confirmed by using molecular methods. Six months after the completion of immunotherapy. HPV DNA was undetectable in skin samples from clinically regressed warts (according to the results of in situ hybridization and polymerase chain reaction). Conclusions: Our patient had treatment- resistant generalized verrucosis for 13 years. Treatment with granulocyte- macrophage colony-stimulating factor and IFN-γ may have reconstituted an immune response against HPV, resulting in the dramatic regression of her widespread warts.