Human papillomavirus-induced infections may be associated with cellular immunodeficiency. However, very little is known about the dysfunctional interactions among T lymphocytes, B lymphocytes, and antigen-presenting cells. A 30-year-old heterosexual man with a 10-year history of persistent multiple refractory flat wart lesions containing human papillomavirus type 3-related DNA sequence was studied. The patient had a severe depletion of CD4+ T lymphocytes and a compensatory increase in the number of CD8+ T lymphocytes. Impaired T-lymphocyte response to various stimuli was found. Depletion of the increased number of CD8+ T lymphocytes, which suppressed immunoglobulin production in vitro, did not restore the impaired T-lymphocyte response. Immobilized anti-CD3 beads that stimulate the T lymphocyte antigen complex in the absence of antigen-presenting cells indicated a T-lymphocyte defect, rather than a decreased antigen-presenting cell function. Thus, the pronounced cellular immunodeficiency was due to abnormal function of the CD4+ helper/inducer T lymphocytes.