The FAS (CD95/APO-1) receptor and its ligand play an important role in the initiation of apoptosis under many physiologic conditions. Loss of function mutations of the FAS gene have been described in lpr mice and in humans with autoimmune phenomena, recurrent lymphadenopathies, and hepatosplenomegaly. This syndrome is now called autoimmune lymphoproliferative syndrome type I (ALPS I). Recently, patients with similar clinical symptoms due to a functional FAS deficiency without FAS gene mutations have been distinguished. This disease has been termed autoimmune lymphoproliferative syndrome type II (ALPS II) or autoimmune lymphoproliferative disease (ALD). This report is the first description of the lymph node pathology and immunohistochemistry in a patient with ALPS II. After recurrent bacterial infections, a 4-year-old child developed cervical giant lymphadenopathy suggesting lymphoma. Lymph node histology resembled the findings in Epstein Barr virus-associated posttransplant atypical lymphoproliferations. Confluent sheets of immunoblasts, however, showed a monoclonal expression of IgG/lambda and a monoclonal rearrangement of the JH chain. The same clone was also present in the peripheral blood. Although high-grade lymphoma could not be excluded, the patient's parents insisted on the patient's leaving the hospital with only antibiotic treatment. Surprisingly, the giant lymphadenopathy completely resolved within 7 weeks, and the clone was no longer detectable in the peripheral blood. Twelve months later the patient was still free from lymphoma and was doing well. Retrospectively, transient monoclonal B-cell populations could be identified in an archival frozen blood sample taken when the patient was 3 years old. Increased FAS-independent spontaneous apoptosis was a feature of the patient's lymphocytes and could be the molecular basis for self-elimination of B-cell clones. We conclude that the diagnosis of a FAS-FAS-L deficiency should be considered in children with an otherwise unexplained atypical lymphoproliferation and that a diagnosis of lymphoma in patients with functional FAS deficiency should be made with considerable reservation.