Introduction: Idiopathic short stature (ISS) is a common pediatric condition. While pegylated recombinant human growth hormone (PEG-rhGH) is a validated treatment, its efficacy and safety under varied dosing regimens in ISS patients remain unreported. Objectives: This prospective, open-label, multicenter, randomized controlled trial (ChiCTR2400087245) evaluated the efficacy and safety of PEG-rhGH at different dosage levels in children with ISS. Methods: This clinical trial planned to enroll 100 children with ISS meeting inclusion and exclusion criteria. After randomization, patients received treatment strategies with different drug doses (0.2, 0.25, or 0.3 mg/kg/week) and underwent continuous follow-up. Changes in height standard deviation scores (△Ht SDS) and various clinical and biochemical safety indicators were monitored pre-treatment and post-treatment to evaluate the efficacy and safety of different dosing strategies, aiming to explore more scientifically effective administration regimens. Results: A total of 100 eligible children were enrolled, with no significant differences in baseline characteristics observed across dosage groups. A dose-response trend was observed at the 26-week follow-up, with greater increases in △Ht SDS at higher dosages (0.25 vs 0.2 mg/kg/week: LSM difference 0.12 [95% CI: 0.01 to 0.23], P = 0.033; 0.3 vs 0.2 mg/kg/week: LSM difference 0.17 [95% CI: 0.06 to 0.28], P = 0.004). Safety indicators, including IGF-1 levels, bone age, and glucose metabolism indicators, showed no significant differences among groups. Conclusions: PEG-rhGH starting doses of 0.25 and 0.3 mg/kg/week demonstrated superior efficacy and safety in children with ISS. These findings provide clinical guidance for dose optimization of PEG-rhGH in ISS treatment.