Our previous studies of the translocated MYC gene in Burkitt's lymphoma showed the existence of clustered somatic mutations located in the transcriptional activation domain. We now report that aggressive lymphomas arising in the acquired immunodeficiency syndrome (AIDS) contain similar mutations and that the presence of mutations is correlated with the rearrangement of the oncogene. Mutations were also found in other de novo non-AIDS, non-Burkitt's aggressive lymphomas with MYC rearrangements. An unusual asparagine to serine mutation at codon 11 was identified in several transformed follicular lymphomas without MYC rearrangement but not in normal tissues from patients with this mutation. These findings indicate that AIDS-associated and other de novo aggressive lymphomas with the MYC gene rearrangement are subject to the same mutation and selection process that affects Burkitt's lymphomas.