Background and objectives Based on some previous observational studies, there is a theory that suggests a potential relationship between Helicobacter pylori (H. pylori) colonization and celiac disease (CeD); however, the type of this relationship is still controversial. Therefore, we aimed to conduct a systematic review and meta-analysis to explore all related primary studies to find any possible association between CeD and human H. pylori colonization. Data sources Studies were systematically searched and collected from four databases and different types of gray literature to cover all available evidence. After screening, the quality and risk of bias assessment of the selected articles were evaluated. Synthesis methods Meta-analysis calculated pooled odds ratio (OR) on the extracted data. Furthermore, heterogeneity, sensitivity, subgroups, and publication bias analyses were assessed. Results Twenty-six studies were included in this systematic review, with a total of 6001 cases and 135512 control people. The results of meta-analysis on 26 studies showed a significant and negative association between H. pylori colonization and CeD (pooled OR = 0.56; 95% CI = 0.45–0.70; P < 0.001), with no publication bias (P = 0.825). The L’Abbé plots also showed a trend of having more H. pylori colonization in the control group. Among subgroups, ORs were notably different only when the data were stratified by continents or risk of bias; however, subgroup analysis could not determine the source of heterogeneity. Conclusions According to the meta-analysis, this negative association might imply a mild protective role of H. pylori against celiac disease. Although this negative association is not strong, it is statistically significant and should be further considered. Further investigations in both molecular and clinic fields with proper methodology and more detailed information are needed to discover more evidence and underlying mechanisms to clear the interactive aspects of H. pylori colonization in CeD patients. Systematic review registration number (PROSPERO) CRD42020167730 https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=167730.

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