Collagen type I is a common structural protein in bone and skin. Similar to its association with the mechanical properties of the skeleton and, thus, bone-fracture risk, the collagen type I alpha (COLIA)-1 specific protein (Sp)-1 polymorphism may be related to variations in the collagen type I-containing subcutaneous tissue and its biological properties. In this study, we analyzed a possible influence of the COLIA1 Sp1 polymorphism on the effect of subcutaneously injected recombinant human growth hormone (hGH) in GH-deficient adults.We determined the COLIA1 Sp1 polymorphism in 122 adults with GH deficiency of different origin, who were derived from the prospective Pfizer International Growth Database (KIMS) Pharmacogenetics Study. Inclusion criteria were subcutaneous applied treatment with hGH for over 12 months, finished dose titration of hGH by following serum IGF-1 concentrations until desired levels were achieved, and centralized, standardized IGF-1 measurements. The genotypes (GG/GT/TT) were statistically related to clinical data from the KIMS database.The dose of injected hGH was significantly related to the COLIA1 Sp1 genotypes (p = 0.049), whereby the GG homozygotes were treated with a significantly higher dose of hGH than TT homozygotes (p = 0.03). Accordingly, the IGF-1:GH ratios were significantly lower in GG compared with TT homozygotes (p = 0.04). Both groups showed no significant differences in their IGF-1 serum concentrations (p = 0.98) and IGF-1 SDS (p = 0.79).The COLIA1 Sp1 polymorphism is related to the dose of individually required, subcutaneous injected hGH in GH-deficient adults, probably because of an alteration of the subcutaneous collagen type I structure, content and/or biological/biomechanical properties. GG homozygotism, which is related to a more stable bone structure and decreased fracture risk, may impact skin resistance to subcutaneous injected protein-based drugs, as shown for hGH in this study.