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Objective: This Italian survey aims to evaluate real-life long-term efficac y and safety of recombinant human growth hormone (rhGH) therapy in children wit h short stature homeobox-containing gene deficiency disorders (SHOX-D) and to id entify potential predictive factors influencing response to rhGH therapy. Design and methods: This is a national retrospective observational study collectin g anamnestic, anthropometric, clinical, instrumental and therapeutic data in children and adolescents with a genetic confirmation of SHOX-D treated on rhG H. Data were collected at the beginning of rhGH therapy (T0), yearly during the first 4 years of rhGH therapy (T1, T2, T3 and T4) and at near-final height (nFH) (T5), when availab le. Results: One hundred and seventeen SHOX-D children started rhGH therapy (initial dose 0.23 ± 0.04 mg/kg/week) at a mean age of 8.67 ± 3.33 years (74% prepubertal), 99 completed the first year of treatment and 46 reached nFH. During rhGH therapy, growth velocity (GV), standard deviation score (SDS) and height (H) SD S improved significantly. Mean H SDS gain from T0 was +1.14 ± 0.58 at T4 and +0.80 ± 0.98 at T5. Both patients carrying mutations involving intragenic SHOX region (group A) a nd ones with regulatory region defects (group B) experienced a similar beneficial therap eutic effect. The multiple regression analysis identified the age at the start of rhGH trea tment (β = −0.31, P = 0.030) and the GV during the first year of rhGH treatment ( β = 0.45, P = 0.008) as main independent predictor factors of height gain. During rhGH thera py, no adverse event of concern was reported. Conclusions: Our data confirm the efficacy and safety of rhGH therapy in SHOX- D children, regardless the wide variety of genotype. Significance Statement: Among children with idiopathic short stature, the prevalence o f SHOX-D is near to 1/1000–2000 (1.1–15%) with a wide phenotypic spectrum. Current guidelines support rhGH therapy in SHOX-D children, but long-te rm data are still few. Our real-life data confirm the efficacy and safety of rhGH therapy in SHOX-D children, regardless of the wide variety of genotypes. Moreover, rhGH the rapy seems to blunt the SHOX-D phenotype. The response to rhGH in the first year of trea tment and the age when rhGH was started significantly impact the height gain.