Western H. pylori cagA+ strains with 2 or more EPIYA-C motifs significantly enhance gastric cancer risk. Our aims were to: 1. verify whether the differences in the degree of inflammation and activity found in cagA+ strains infected patients depend on EPIYA-C or on other H. pylori virulence genes, namely vacA and babA2; 2. ascertain which is the main virulence determinant associated with intestinal metaplasia (IM) and/or atrophy. We studied 191 H. pylori infected patients: 66 cagA- (54 gastritis, 12 duodenal ulcer) and 125 cagA+ (85 gastritis, 40 duodenal ulcer). Antrum and corpus biopsies were obtained for histology and H. pylori culture. The following histological parameters were considered: antrum and corpus inflammation, activity and H. pylori colonization grades and presence or absence of IM and atrophy. The following H. pylori virulence genes were PCR analysed in antrum and corpus isolates: vacA s, i and m polymorphisms and cagA EPIYA-C. babA2 status was studied in antrum isolates. In fasting sera pepsinogen A (PGA) and C (PGC) were assayed (ELISA) to calculate PGA/PGC ratio, a biochemical index of multifocal or corpus atrophy. Both antrum and corpus inflammation and activity were correlated with vacA s1 and i1 alleles and with cagA EPIYA-C motifs (p<0.05); corpus inflammation and activity were also correlated with vacA m1 allele (p<0.05). babA2 was not associated with any of the above parameters. IM was correlated with s1 (p<0.001), i1(p<0.001) and m1 vacA (p<0.001), with EPIYA-C motifs (p<0.001), with babA2 (p<0.01), with corpus inflammation (p<0.05) and H. pylori colonization grade (p<0.005). Only EPIYA-C was confirmed to be correlated with IM at binary logistic regression analysis (p<0.05). Since only a minority of our patients had chronic atrophic gastritis, we biochemically defined the presence (BA) or absence (BN) of multifocal atrophy on the basis of PGA/PGC ratio (<= or >4.7). BA was significantly correlated with s1 vacA (p<0.05), babA2 (p<0.005) and EPIYA-C motifs (p<0.01). Only EPIYA-C motifs were confirmed to be significantly associated with BA at binary logistic regression analysis (p<0.05; 1 EPIYA-C: OR=1.7; 95% CI=0.3-9; two or more EPIYA-C: OR=4.7; 95% CI=1.07-21.18). In 12 patients a different number of EPIYA-C motifs was found between antrum and corpus isolates; this feature did not correlate with any of the studied parameters. In conclusion: among western H. pylori strains virulence determinants, the number of EPIYA-C motifs is mainly associated with IM and with the presence of biochemical sings of atrophy and this fits with an early involvement of multiple EPIYA-C in multistep gastric carcinogenesis.