The success of triple therapy [proton pump inhibitor, clarithromycin, amoxicillin (PCA)] for H. pylori eradication is about 80%. Several bacterial and host related factors concur in causing eradication failure. Our aim was to ascertain the role of bacterial virulence genes (cagA, vacA), clarithromycin resistance (ClaR, 23S rRNA mutations), host polymorphism of genes involved in PPI metabolism (CYP2C19) and in the modulation of host immune response (IFNγ, TNFα, IL1β, IL1RN, IL10, IL12). We selected 100 H. pylori infected patients (histology). All were PCA treated; eradication was evaluated by 13C-UBT. H. pylori DNA was used to PCR analyze the followings: cagA, vacA s and m polymorphisms, five 23S rRNA mutations associated with ClaR. In peripheral blood DNA the following SNPs were assayed: IFNγ+874A>T, TNFα-1031T>C, TNFα-857C>T, TNFα-376G>A, TNFα-308G>A, TNFα-238G>A, IL1β-31C>T, IL1RN intron 2 VNTR, IL10-1082A>G, IL10-819C>T, IL10-592C>A, IL12+6686G>A, IL12+15485A>C, CYP2C19-3402 C>T, CYP2C19-806 C>T, CYP2C19+681 G>A. Eradication failed in 45 cases. ClaR was found in 22/71 H. pylori strains, being more frequent in females than in males (χ2=9.4, p<0.01). Treatment failure was significantly correlated with: ClaR (χ2=10.8, p<0.001, all resistant strains were in non eradicated patients), TNFα-238 (Fisher’s exact test: p<0.05), IL10-819 (χ2=9.0, p<0.01), IL10-592 (χ2=9.0, p<0.01) SNPs and with IL10 ATA/ATA haplotype (Fisher’s exact test: p<0.05). With logistic regression analysis (eradication=dependent, ClaR, TNFα-238 SNP and IL10 ATA/ATA=covariates) only ClaR (Exp(B)=17939,8, 95%CI=0-3.15E+33) and TNFα-238 SNP (Exp(B)=10.5, 95%CI=1.06-105.0) were significant. After selecting patients infected by ClaS strains, eradication correlated with: TNFα-1031 (χ2=8.5, p<0.05), TNFα-238 (Fisher’s exact test: p<0.05) SNPs and with antral activity (χ2=9.5, p<0.01). Logistic regression analysis (eradication=dependent; TNFα-1031 and -238 SNPs, and antral activity=covariates) allowed a correct classification of patients in 81.08% of the cases, only TNFα-238 SNP (Exp(B)=32.8, 95%CI=0.51-2089.9) and antral activity (Exp(B)=0.22, 95%CI=0.04-1.17) being relevant. In conclusion: H. pylori ClaR is the main cause of eradication failure after PCA therapy; ClaR is more frequent in females, possibly because of a larger antibiotics use; CYP2C19 polymorphisms in Italian patients has a minor role in affecting eradication; TNFα-238 SNP affects eradication success, probably because it might be involved both the control of gastric acid secretion and in the inflammatory response, the degree of which in antral mucosa is one of the parameters influencing eradication therapy efficacy.