Background: Gingival enlargement (GE) is one of the most common soft tissue problems encountered during fixed orthodontic treatment. Aims: This studs aimed to evaluate the factors affecting GE in adolescents and young adults, compared with their normal peers. Subjects and Methods: This is a cross-sectional comparative study. The sample consisted of 329 subjects (ages 10-30 years) of both genders, which was divided into four main groups: The control group (GO) with no orthodontic treatment; subjects who underwent orthodontic treatment were divided according to treatment duration into G1 (4-12 months), G2 (13-24 months), and G3 (>24 months). The clinical examinations included the level of debris, calculus (simplified oral hygiene), and GE indices. Regression analyses were used to assess the GE association in all the studied groups. Results: The mean GE score increased significantly with increased treatment duration (0.42 +/- 0.29 for G0 and 1.03 +/- 0.52 for G3). GE scores of the lower arch were significantly higher in the anterior segment than in the posterior segment among all treatment groups. Regression analysis revealed that gender, age, oral hygiene, and treatment duration had a significant effect on GE (P < 0.05), while angle classification, overjet, overbite, treatment stage, bracket type, and therapeutic extraction did not show significant associations (P > 0.05). Conclusion: Gender, age, oral hygiene, and treatment duration were the most important risk factors for GE during fixed orthodontic treatment.