There is significant heterogeneity in serum IGF-I concentrations among normal healthy individuals across all ages and among inbred strains of mice. C3H/HeJ (C3H) mice have 30% higher serum IGF-I concentrations over a lifetime than C57BL/6J (B6), even though body size and length are identical. The underlying mechanism for this disparity remains unknown although several possibilities exist including altered GH secretion, resistance to GH action, or impaired IGF-I secretion from the liver or peripheral tissues. To study this further, we evaluated mRNA levels of pituitary GH, and of IGF-I, GH receptor (GHR) and acid-labile subunit (ALS) in liver and skeletal muscle of male C3H and B6 strains. mRNA levels of hepatic IGF-I paralleled serum IGF-I levels, whereas pituitary GH mRNA expression was significantly lower in C3H than B6. In addition, reduced hepatic mRNA levels of ALS and GHR in B6 suggests hepatic GH resistance in B6. In contrast, mRNA levels of IGF-I and GHR in skeletal muscle were not different between B6 and C3H. There was a single sequence repeat polymorphism (SSR) in the promoter region of both GHR and IGF-I genes in mice; the SSR in the IGF-I gene was significantly different between the two strains. The SSR in the IGF-I gene corresponds to the E2F binding site, which is critical for regulating IGF-I gene expression. These results suggest that the SSR in the promoter region of the IGF-I gene may be partially responsible for differences in serum IGF-I levels between B6 and C3H strains.