The prevalence of multiple independent primary cancer of the stomach is high in Japanese. We hypothesized that individuals with multiple, independent gastric cancers might have a greater genetic susceptibility than persons with solitary gastric cancer at the time of diagnosis. We therefore determined the frequency of mutator phenotypes in 20 persons with independent multiple gastric cancers and 42 persons with solitary primary lesions. The mutator phenotype was determined by examining dinucleotide CA repeats at the microsatellite loci D2S136 (chromosome 2), MSX2 (chromosome 5q34), D5S82 (chromosome 5q14-21) and TP53 (chromosome 17p13.1). Although there were no significant differences between the clinical and pathological features (stage or histopathological subtype) of the two groups, the prevalence of any one microsatellite instability in patients with multiple gastric cancer was greater (65% versus 24%; P = 0.003) than in those with solitary gastric cancer. The prevalence of co-occurrence of mutator phenotype in synchronous lesions was greater than expected based on their frequency in solitary gastric cancer (12% versus 9% x 9%). Persons with advanced-stage multiple primary lesions were more likely to exhibit the mutator phenotype (P = 0.10). These findings indicate that individual predisposition for qualitative or quantitative defects in DNA repair systems significantly contribute to the simultaneous occurrence of gastric cancer in Japanese.