The effect of 40% food restriction (FR) and replenishment on the growth hormone (GH) and insulin-like growth factor-I (IGF-I) axis in the epiphyseal growth plate (EGP) was examined in a mouse model. Changes in RNA and protein levels were evaluated with real time PCR and immunohistochemistry, respectively, and serum levels of IGF-I and leptin were measured with radioimmunoassay. Dramatic changes in weight, tibial length and EGP height were observed following 10 days of 40% FR. The protein levels of IGF-I receptor (IGF-IR) and GH receptor (GHR), which were reduced during FR, increased during catch-up growth without an apparent change in the level of their RNA. The levels of type II and X collagens were unchanged. Serum IGF-I and leptin levels were reduced during FR and increased during catch-up growth. Following 40% FR, there was a significant decrease in the level of GHR and IGF-IR in the EGP which may explain the reduced effect of GH treatment in malnourished animals and children.