The American Burkitt Lymphoma Registry (ABLR) investigates the cause of Burkitt's lymphoma through comparative studies involving endemic and nonendemic regions. In 3 years 114 cases have been confirmed. Diagnosis was based on evaluation of pathologic materialy submitted to ABLR pathologists. Similarities between American and African patients included abrupt clinical presentation with involvement of the gastrointestinal tract, jaw, gonads, and central nervous system. Response to high-dose cyclophosphamide and an apparent high cure rate distinguish American Burkitt's lymphoma from poorly differentiated lymphocytic lymphoma (lymphosarcoma) of childhood. Time-space clustering and absence of cases in high-altitude regions are seen in American and African patients; young American patients resemble Africans in a predominance of men and high Epstein-Barr virus titers. American patients have bone-marrow and peripheral lymph-node involvement more frequently and are less likely to have Epstein-Barr virus genome in their tumors; most are white. Identification of specific causal factors requires the study of more cases and better pretreatment material for pathologic review.