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Background: Pepsinogen (PG) II (PGII) is a serological marker used to estimate the risk of gastric cancer but how PGII expression is regulated is largely unknown. It has been suggested that PGII expression, from the <i>PGC</i> (Progastricsin) gene, is regulated by microRNAs (miRNA), but how PGII levels vary with <i>Helicobacter pylori (H. pylori)</i> infection and miRNAs genotype remains unclear. Methods: Serum levels of PGI and PGII were determined in 80 patients with gastric cancer and persons at risk for gastric cancer (74 first-degree relatives of patients, 62 patients with autoimmune chronic atrophic gastritis, and 2 patients with dysplasia), with and without <i>H. pylori</i> infection. As control from the general population, 52 blood donors were added to the analyses. Associations between PGII levels and genetic variants in <i>PGC</i> and miRNA genes in these groups were explored based on <i>H. pylori</i> seropositivity and the risk for gastric cancer. The two-dimensional difference in gel electrophoresis (2D-DIGE) and the NanoString analysis of messenger RNA (mRNAs) from gastric cancer tissue were used to determine the pathways associated with increased PGII levels. Results: PGII levels were significantly higher in patients with gastric cancer, and in those with <i>H. pylori</i> infection, than in other patients or controls. A PGI/PGII ratio ≤ 3 was found better than PGI < 25 ng/mL to identify patients with gastric cancer (15.0% vs. 8.8%). For two genetic variants, namely rs8111742 in miR-Let-7e and rs121224 in miR-365b, there were significant differences in PGII levels between genotype groups among patients with gastric cancer (<i>p</i> = 0.02 and <i>p</i> = 0.01, respectively), but not among other study subjects. Moreover, a strict relation between rs9471643 C-allele with <i>H. pylori</i> infection and gastric cancer was underlined. Fold change in gene expression of mRNA isolated from gastric cancer tissue correlated well with polymorphism, <i>H. pylori</i> infection, increased PGII level, and pathway for bacteria cell entry into the host. Conclusions: Serum PGII levels depend in part on an interaction between <i>H. pylori</i> and host miRNA genotypes, which may interfere with the cut-off of PGI/PGII ratio used to identify persons at risk of gastric cancer. Results reported new findings regarding the relation among <i>H. pylori</i>, PGII-related host polymorphism, and genes involved in this interaction in the gastric cancer setting.