Based upon in vitro evidence of p53 involvement in lymphoid differentiation, we assessed immunoglobulin (Ig) and T-cell receptor (TCR) genes in five acute lymphoblastic leukemias (ALLs) with, and 24 ALLs without p53 mutations to compare their genotypic stages. Using Southern blot analysis and complementarity determining region III polymerase chain reaction (CDRIII PCR), 18 cases of B-lineage ALL and 11 cases of T-ALL were studied. Of 20 specimens from 18 B-lineage ALLs, two of four with p53 mutation and two of 16 without mutation had an unrearranged Ig and TCR genotype (p = 0.16; Fisher's exact test). Of 11 cases of T-ALL, the one case with p53 mutation had a rearranged TCR and Ig genotype and a case without mutation was unrearranged. The study indicates that p53 mutation is an infrequent feature of ALL found, nonetheless, in every genotypic subset. The p53 mutations in cases that do not further rearrange may support p53 involvement in lymphoid differentiation, but the heterogeneity in differentiation stages in cases both with and without p53 mutations suggests that regulation of early lymphoid maturation is multifactorial.