Available evidence suggests that, among hematological malignancies, p53 is most often mutated in Burkitt's lymphoma (BL). However, much of the published data is based on cell lines. We have, therefore, analyzed BL biopsies to determine more accurately the frequency and pattern of p53 mutations in primary tumors and to determine whether there are differences among the various subtypes of BL. Among 27 BL biopsies from South Africa, we have observed mutations in the p53 gene (exons 5 through 8) in 37% of tumors. The higher frequency of mutations in cell lines (70%) suggests that mutation of p53 may be associated with tumor progression. Summarizing available data we conclude that the presence of mutated p53 in BL is independent of the geographic origin of the tumor, the 8;14 chromosomal breakpoint locations and Epstein-Barr virus association. We also find that the mutational spectrum of p53 in BL differs from that observed in nonlymphoid tumors. More than 50% of mutations in BL are clustered in a small stretch of 33 amino acids (codons 213 to 248). Interestingly, codon 213 appears to be as frequently mutated as codon 248. Conversely, codon 273, often mutated in solid tumors, is rarely involved in BL.