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Background: Few studies have compared the response to growth hormone (GH) treatment between indications such as isolated growth hormone deficiency (IGHD), born small for gestational age (SGA), idiopathic short stature (ISS), and multiple pituitary hormone deficiency (MPHD). The aim of this analysis of data, collected from two large ongoing observational outcome studies, was to evaluate growth and insulin-like growth factor-I (IGF-I) response data for children of short stature with IGHD, MPHD, SGA, or ISS following two years of treatment with the recombinant GH product Norditropin® (Novo Nordisk A/S, Bagsværd, Denmark). Methods: Analysis of auxologic data from two ongoing prospective observational studies, NordiNet® International Outcomes Study (NordiNet® IOS) and NovoNet®/American Norditropin® Studies: Web-enabled Research (ANSWER) Program®. Results: 4,582 children aged <18 years were included: IGHD, n = 3,298; SGA, n = 678; ISS, n = 334; and MPHD, n = 272. After two years' GH treatment, change in height standard deviation score (SDS) was +1.03 in SGA and +0.84 in ISS vs. +0.97 in IGHD (p=0.047; p<0.001 vs. IGHD, respectively). Height gain was comparable between IGHD and MPHD. In pre-pubertal children vs. total population, height SDS change after two years was: IGHD, +1.24 vs. +0.97; SGA, +1.17 vs. +1.03; ISS, +1.04 vs. +0.84; and MPHD, +1.16 vs. +0.99 (all p<0.001). Conclusions: After two years' GH treatment, change in height SDS was greater in SGA and less in ISS, compared with IGHD; the discrepancy in responses may be due to the disease nature or confounders (i.e. age). Height SDS increase was greatest in pre-pubertal children, supporting early treatment initiation to optimize growth outcomes. [ABSTRACT FROM AUTHOR]