AIM: To explore the long-term efficacy, safety, and optical mechanism of orthokeratology with increased compression factor in adolescent myopia control. METHODS: A prospective, double-masked, and randomized clinical trial was performed from May 2016 to June 2020. Subjects aged between 8 and 16y, with myopia (-5.00 to -1.00 D), low astigmatism (≥-1.50 D) and anisometropia (≤1.00 D), were stratified into low (-2.75 to -1.00 D) and moderate (-5.00 to -3.00 D) myopia groups. Then they were randomly assigned to wear either increased compression factor (ICF; 1.75 D) orthokeratology or conventional compression factor (CCF; 0.75 D) orthokeratology. The data were recorded including axial length (AL), spherical equivalent (SE), best corrected visual acuity (BCVA), near visual acuity (NVA), corneal staining (using Efron grading scales), corneal hysteresis (CH), corneal resistance factor (CRF), higher-order aberrations (HOAs, expressed as root mean square, RMSh), and subfoveal choroidal thickness (SFChT) in the 2-year follow-up period. Pearson’s correlation coefficient was conducted to analyze the association between the changes in AL and RMSh, SFChT. RESULTS: At the 2-year visit, there were no statistical differences in all the parameters between the ICF group and the CCF group in low myopia subjects (P>0.05). For the moderate myopia subjects, the ICF group had shorter AL elongation (0.23±0.08 vs 0.30±0.11 mm, P=0.015), higher RMSh (1.94±0.50 vs 1.65±0.51 μm, P=0.041), and higher SFChT (279.04±35.72 vs 254.08±29.60 μm, P=0.008) than those in CCF group. The change in AL was negatively correlated with RMSh (r=-0.687, P<0.001) and SFChT (r=-0.464, P=0.013). CONCLUSION: ICF orthokeratology can control the progression of moderate myopia more effectively, which might be related to greater RMSh and SFChT.