A detailed analysis of p53 (TP53) mutations involving the 42 CpG dinucleotides was performed to gain greater insight into the mutational mechanism leading to specific selection of these mutations. Although the majority of these CpG dinucleotides have been found to be mutated in cancer cells, the heterogeneous frequency of mutational events suggests that some mutations are not true mutations, but neutral changes that have been co-selected during oncogenic transformation. Among the 1,400 variants found in the 15,000 mutations of the p53 database, 5% have only been described once, indicating that either the mutational event is rare, or the mutation phenotype is very mild, or both. Overall, these data indicate that great caution is required when analyzing the significance of p53 mutations. Hum Mutat 21:192–200, 2003. © 2003 Wiley-Liss, Inc.