AimPeri‐implant mucositis, a dysbiosis‐driven inflammatory disease, is a precursor to peri‐implantitis, underscoring the need for early disease management. Therefore, we investigated the efficacy of glycine powder in resolving clinical inflammation and restoring host‐microbial homeostasis.MethodsThirty subjects were randomized to receive either glycine powder air‐abrasive debridement or ultrasonic instrumentation. Clinical parameters (probe depth [PD], modified Sulcular Bleeding Index [mSBI], modified Plaque Index [mPlI]), biofilm and peri‐implant crevicular fluid were collected at baseline and at 1‐day, 1‐, 3‐, 6‐weeks and 3‐ and 6‐months post‐therapy. Microbial recolonization was examined using 16S rDNA sequencing and immune response was semi‐quantified using a bead‐based 17‐plex microarray.ResultsAt 6‐months, both groups demonstrated non‐significant reductions in mSBI when compared to baseline (p > 0.05, Wald test, mixed model for repeated measures). However, mSBI and PD decreased in the test group from week‐1 to 3‐months, while control group decreased at 1‐ and 3‐weeks only. mSBI was lower in the test group when compared to controls from Week‐1 to 3‐months, while PD differed between groups at 6 weeks and 3‐months. Glycine group demonstrated significant microbial shifts after 24‐h, increases in species richness and health‐compatible species, and loss of pathobionts (p < 0.001, Dunn test). Pro‐inflammatory cytokines decreased from 1‐ to 6‐weeks or 3‐months (p < 0.05, Wald test). Comparable results were obtained in the ultrasonic group at 3‐weeks and sustained over 6‐weeks post‐therapy.ConclusionsGlycine therapy leads to early and sustained change in host‐microbial interactions when compared to ultrasonics, however, the changes wrought by both therapies were sustained for a maximum of 3 months.Trial RegistrationClinicalTrials.gov identifier: NCT05810558