Abstract Objective Investigate efficacy, safety, and tolerability of 3 once-weekly somapacitan doses compared with daily growth hormone (GH) administration in short children born small for gestational age (SGA). Design Randomised, multi-centre, open-label, controlled phase 2 study comprising a 26-week main phase and a 4-year extension (NCT03878446). The study was conducted at 38 sites across 12 countries. 26-week main phase results are presented here. Sixty-two GH treatment-naïve, prepubertal short children born SGA were randomised and exposed; 61 completed the main phase. Three somapacitan doses (0.16 [n = 12], 0.20 [n = 13], 0.24 [n = 12] mg/kg/week) and 2 daily GH doses (0.035 [n = 12], 0.067 [n = 13] mg/kg/day) were administered subcutaneously. Results After 26 weeks of treatment, the estimated mean annualised height velocity (HV) was 8.9, 11.0, and 11.3 cm/year for somapacitan 0.16, 0.20, and 0.24 mg/kg/week, respectively, compared to 10.3 and 11.9 cm/year for daily GH 0.035 and 0.067 mg/kg/day. Changes from baseline in HV standard deviation score (SDS), height SDS, and insulin-like growth factor I (IGF-I) SDS showed similar dose-dependent responses. Exposure-response modelling indicated the greatest efficacy correlated with the highest somapacitan exposure. Similar safety and tolerability were demonstrated for all weekly somapacitan and daily GH doses. Conclusions Based on the totality of data on improvements in height-based parameters combined with exposure-response analyses, somapacitan 0.24 mg/kg/week appears most efficacious, providing similar efficacy, safety, and tolerability as daily GH 0.067 mg/kg/day in short children born SGA after 26 weeks of treatment.