p53 is one of the most mutated genes in human cancer. We have performed the molecular characterization of p53 and have searched for correlations with etiological factors and clinical parameters in primary and secondary liver tumors. A systematic study was carried out, innovative in many respects, to determine the mutational pattern of all 11 exons of p53 and analysis was extended also to exons 1-4 and 9-11 and the exon/intron junctions. Our analyses were performed on case histories of 114 patients from the European area and highlighted p53 mutation patterns different from those reported in the literature for the same tumors. In our case history, different tumors of the same organ showed a different frequency and distribution of mutations. In analyzed tumor types, gene status was a prognostic indicator of survival because patients undergoing liver resection without mutated p53 had a more favorable prognosis than mutated patients. This suggests p53 molecular diagnosis could become a further criterion in the decision for surgery and possible therapies. We describe the ideal conditions for polymerase chain reaction (PCR), single-strand conformation polymorphism (SSCP), and direct sequencing, which we have set in order to optimize yields, sensitivity, and time of what might become a massive molecular screening.