Background and aims Spasmolytic polypeptide‐expressing metaplasia (SPEM) is a preneoplastic gastric cancer lesion related to epigenetic microRNA (miRNA) expression. This study elucidated whether Helicobacter pylori‐infected first‐degree relatives of patients with gastric cancer (GCF) are susceptible to have SPEM and correlated with miR‐21, 155, and 223 expressions. We also validated whether SPEM and these miRNAs can be regressed after H pylori eradication. Methods We prospectively enrolled 148 GCF and 148 nonulcer dyspepsia (NUD) subjects without gastric cancer familial history as controls. Each case had received a panendoscopy to determine H pylori status and gastric histology, including SPEM. The cases with SPEM were followed after H pylori eradication to determine SPEM regression. The total RNA was extracted to analyze tissues miR‐21, 155, and 223 before and after eradication. Results GCF subjects had a higher prevalence of H pylori infection (73% vs 32%) and SPEM (42% vs 14%, P < 0.01) than controls. The tissue miR‐21, 155, and 223 in antrum were higher in cases with SPEM than in those without SPEM (P <= 0.05). There was similar SPEM reversibility after H pylori eradication between GCF subjects and controls (72% vs 69%, P = 0.852). In the SPEM regressed cases, tissue miR‐21, 155, and 223 decreased after H pylori eradication (P < 0.05). Conclusion The H pylori‐infected GCF subjects were prone to have SPEM with higher tissues miR‐21, 155, and 223 expressions. H pylori eradication can result in a 70% SPEM regression, accompanied by a decline in miR‐21, 155, and 233 expression levels.