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Purpose: To investigate axial elongation (AE) and changes in relative peripheral refraction (RPR) in anisomyopic children undergoing orthokeratology (ortho‐k). Methods: Bilateral anisomyopic children, 7–12 years of age, were treated with ortho‐k. Axial length (AL) and RPR, from 30° nasal (N30°) to 30° temporal (T30°), were measured at baseline and every 6 months over the study period. AE, changes in RPR and changes in the interocular AL difference were determined over time. Results: Twenty‐six of the 33 subjects completed the 2‐year study. The AE of the higher myopic (HM) eyes (at least 1.50 D more myopia than the other eye) (0.26 ± 0.29 mm) was significantly smaller than for the less myopic (LM) eyes (0.50 ± 0.27 mm; p = 0.003), leading to a reduction in the interocular difference in AL (p = 0.001). Baseline RPR measurements in the HM eyes were relatively more hyperopic at T30°, N20° and N30° (p ≤ 0.02) and greater myopic shifts were observed at T20° (p < 0.001), T30° (p < 0.001), N20° (p = 0.02) and N30° (p = 0.01) after lens wear. After 2 years of ortho‐k lens wear, temporal–nasal asymmetry increased significantly, being more myopic at the temporal locations in both eyes (p < 0.001), while AE was associated with the change in RPR at N20° (β = 0.134, p = 0.01). The interocular difference in AE was also positively associated with the interocular difference in RPR change at N30° (β = 0.111, p = 0.02). Conclusions: Ortho‐k slowed AE in bilateral anisomyopia, with slower growth in the HM eyes leading to a reduction in interocular AL differences. After ortho‐k, RPR changed from hyperopia to myopia, with greater changes induced in the HM eyes, and slower AE was associated with a more myopic shift in RPR, especially in the nasal field of both eyes. [ABSTRACT FROM AUTHOR]