Burkitt's lymphoma (BL) is a malignancy of B cells characterized by chromosomal translocations involving the immunoglobulin (Ig) and c-MYC gene loci. To address the putative role of antigen in the clonal expansion of these neoplastic B cells, we analyzed the VHDJH and VLJL gene segments expressed by the established cell lines derived from six endemic BL and six sporadic BL. Eight BL cell lines used genes of the VH3 family, two of the VH4, and two of the VH1. Eight VL chains were kappa (four members of the V kappa3, two of the V kappa1, and two of the V kappa2 subgroups) and four lambda (three members of the V lambda1 and one of the Vl ambda3 subgroup). The VH gene utilization was stochastic (i.e., it reflected the relative representation of the different VH gene family members in the human haploid genome). In contrast, the VL gene utilization was skewed toward the overutilization of the V kappa3 and V lambda1 gene subgroups. When compared with those of the respective germline genes, the sequences of the expressed Ig VDJ genes displayed nucleotide differences that resulted from somatic hypermutation. In three endemic and three sporadic BL cells, nucleotide changes yielding amino acid substitutions segregated within the complementarity determining region, indicating the application of a positive pressure for replacement mutations and suggesting that these neoplastic lymphocytes underwent a process of clonal selection driven by antigen, perhaps emerging from or transitioning through germinal centers.