Abstract Background Somapacitan is a once-weekly GH treatment that has shown efficacy and safety profiles equivalent to daily GH in children with GH deficiency (GHD). Objective To investigate long-term safety, efficacy, and treatment burden associated with somapacitan after 7 years (364 weeks) of treatment. Methods REAL 3 (NCT02616562) was a phase 2, randomized, open-label trial investigating the efficacy and safety of somapacitan vs daily GH in children with GHD. After 156 weeks, participants entered a 208-week safety extension. Children in cohort I (age 2.5-10.0 years) previously completed 3 years in the trial; cohort II (age <2.5 years) and cohort III (age 9.0-17.0 years) entered the trial at week 156 for safety-only assessment. All participants received somapacitan 0.16 mg/kg/week. Height velocity (HV), HV SD score (SDS), height SDS, IGF-I SDS, incidence of adverse events (AEs), and treatment burden were assessed. Results Overall, 43 participants (73%) in cohort I, 1 participant (100%) in cohort II, and 11 participants (69%) in cohort III completed the 208-week safety extension. Consistent increments in HV and HV SDS were seen in cohort I, and height SDSs at week 364 were close to 0. The incidence of AEs was aligned with previous investigations across all cohorts; 3 serious AEs in cohort I were considered probably/possibly related to treatment. Treatment burden was reduced in children who switched from daily GH to somapacitan. Conclusion After 7 years of treatment, children with GHD receiving somapacitan experienced consistent increases in height SDS and reduced treatment burden. No new safety concerns were identified.