We hypothesize that genomic instability plays an important role in causing specific types of p53 mutations in ovarian cancer. To test this hypothesis, 78 tumors were analyzed for p53 mutations with SSCP analysis of the entire open reading frame. At the same time, alterations in 10 microsatellite loci including di-, tri-, and tetranucleotide repeats were evaluated. Fourteen (26%) of all mutations were insertion/deletion mutations. All insertion/deletion mutations were associated with one of the following features: runs of purines or pyrimidines, repeats of short sequences, or palindromes. There was a strong association of generalized microsatellite instability with p53 in contrast to tumors with other types of mutations or wild-type p53 (P = 0.007). These characteristic p53 mutations appear to be caused by generalized genomic instability rather than to be the direct cause of genomic instability. These findings suggest the existence of additional novel DNA repair genes important to the carcinogenic process.