Mutations in the p53 tumor suppressor gene occur with a frequency of 12.5% in lymphoid malignancies. The viral-associated diseases, Adult T-cell Leukemia (ATL) and Burkitt's lymphoma, showed higher p53 mutation frequencies of 24% and 41%, respectively. Mutations occurred in the highly conserved regions of the p53 gene. Two new hot spots for mutation were noted in exon 7 at codons 239 and 245. The spectrum of p53 mutations differs among different cancers. Transition mutations occurring in colon and brain tumors also predominated in the majority of the lymphoid malignancies. However, B-cell chronic lymphocytic leukemia (B-CLL) and non-Hodgkin's lymphoma (NHL) had an unusually high frequency of G to T transversions. Among carcinomas of the lung, liver, breast and esophagus there is also a high frequency of G to T transversions. The differences in mutation spectra between different lymphoid diseases may be due to differences in mutagenic factors or differences in the biological properties of the p53 protein in different lymphoid compartments. Mutation of the p53 gene is associated with advanced stage of lymphoid disease and poor prognosis. For B-CLL disease, p53 mutations are associated with drug resistance. Overexpression of the bcl-2 protein is also associated with a block in apoptosis. Resistance to apoptosis could be a general mechanism for drug resistance in B-CLL and other lymphoid diseases.