BackgroundThe aim of our study was to evaluate the effects of a hyaluronic acid (HA) gel at 45 days on the microbiome of implants with peri‐implantitis with at least 1 year of loading.MethodsA randomized controlled trial was conducted in peri‐implantitis patients. Swabs containing the samples were collected both at baseline and after 45 days of treatment. 16S rRNA sequencing techniques were used to investigate the effect of HA gel on the subgingival microbiome.ResultsOne hundred and eight samples of 54 patients were analyzed at baseline and after follow‐up at 45 days. Three strata with different microbial composition were obtained in the samples at baseline, representing three main microbial consortia associated with peri‐implantitis. Stratum 1 did not show any difference for any variable after treatment with HA, whereas in stratum 2, Streptococcus, Veillonella, Rothia, and Granulicatella did decrease (P < 0.05). Similarly, Prevotella and Campylobacter (P < 0.05) decreased in stratum 3 after treatment with HA. Microbial diversity was found to be decreased in stratum 3 (P < 0.05) after treatment with HA compared with the control group, in which an increase was found (P < 0.05).ConclusionsHA reduced the relative abundance of peri‐implantitis‐related microorganisms, especially the early colonizing bacteria, suggesting a specific action during the first stages in the development of the disease. HA did not alter relative abundances of non‐oral genera. The use of HA in advanced stages of peri‐implantitis resulted in a decrease in microbial alpha diversity, suggesting a protective action of the peri‐implant site against bacteria colonization.