We have studied, at a molecular level, two small non-cleaved cell malignant lymphomas (Burkitt's type) that were separated by a disease- free interval of 3 years in a patient infected with the human immunodeficiency virus (HIV). The late occurrence of the apparent relapse suggested that the second lymphoma might be caused by a separate malignant transformation in a discrete clone of B cells. Although both tumors expressed the same immunologic surface markers (mu k) and carried the same t(8;14) translocation, Southern blot analysis of DNA from each tumor, using specific restriction endonucleases and probes to the c-myc and the immunoglobulin heavy chain loci, demonstrated that the chromosomal breakpoints relevant to the translocations differed between the tumors. This was corroborated by analysis of the immunoglobulin light-chain rearrangements in the two tumors. These observations indicate that the second tumor was not a recurrence of the first but represented the malignant transformation of a different clone of B cells. Thus late relapses of certain malignancies in individuals at high risk may be caused by the malignant transformation of discrete cell clones (i.e., induction of a new tumor).