Background: The plasminogen activator inhibitor-1 (PAL-1) plays an important role in the pathogenesis of cancer. The 4G/5G promoter polymorphism of PAI-1 is potentially involved in regulating gene transcription. Aims: To explore the role of the PAL-1 4G/5G repeat as target of microsatellite instability (MSI), 50 gastric carcinomas (GCs), characterized for MSI, were screened. Methods: PAI-1 4G/5G was analysed by direct sequencing. Results: Allelic imbalance was observed in 5 of the 50(10%) GCs. Specifically, 2 cases (40%) harboured a G deletion and 3(60%) a G insertion in tumour compared to normal DNA. These five cases were included in the subgroup of 20 GCs (25%) with high level of MSI (MSI-H). A statistically significant association emerged between PAL-1 mutations and MSI-H status (p = 0.0073). The frequency of PAL-1 mutations was also evaluated, together with other known target genes, by analysing MSI-H GCs for mutations at selected coding repeats within genes controlling cell growth, apoptosis and DNA repair. Overall, mutation frequency ranged from 56.3% to 5.3%. Conclusion: The frequency of PAL-1 mutations here reported in MSI-H GCs is, accordingly, comparable with values obtained for real targets. The relatively high incidence of PAL-1 mutations is suggestive of a positive pressure towards selection in MSI-H GCs. (C) 2010 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.