Objectives <p>This prospective study aimed to evaluate periodontal inflammation in adolescents undergoing orthodontic treatment with clear aligners (Invisalign® Teen, Align Technology, San Jose, CA, USA). Key objectives included assessing the presence of 11 periodontitis-associated marker bacteria, active matrix metalloproteinase-8 concentrations in sulcular fluid, and the influence of IL-1 polymorphism genotypes on periodontal health.</p> Materials and methods <p>Fifty adolescent patients (13.3 ± 1.8&#xa0;years) with mixed and permanent dentition participated. Gingival crevicular fluid samples were analyzed at multiple time points: before, during, and one year after aligner treatment. Periodontal health was assessed using the Gingivitis Index and the Modified Quigley-Hein Index. Genotypic analysis of IL-1 polymorphism was also performed. Statistical analyses included mixed linear models and generalized linear models to explore correlations.</p> Results <p>All combinations of IL-1 polymorphism genotypes were found in the sample. No significant increase in periodontal inflammation or aMMP-8 concentrations was observed over the treatment period. Marker bacteria from the red and orange-associated complexes remained at low levels, while significant changes occurred in the orange and green complexes, particularly&#xa0;Capnocytophaga spp.&#xa0;(p = 0.0042) and&#xa0;Fusobacterium spp.&#xa0;(p = 0.0365). GI correlated significantly with aMMP-8 levels (p = 0.0017), but no genotype effect on GI was observed. MQH showed associations with pathogens from the orange and green complexes, including&#xa0;Capnocytophaga spp.&#xa0;and&#xa0;Fusobacterium spp.</p> Conclusions <p>Clear aligner treatment in adolescents, including those with an unfavorable genotype, does not increase periodontal inflammation when accompanied by good oral hygiene.</p> Clinical relevance <p>Regular periodontal monitoring and hygiene reinforcement is important during orthodontic treatment, especially in adolescent patients.</p>