Adults with growth hormone deficiency (GHD) exhibit low bone mineral density (BMD) which improves by growth hormone (GH) replacement therapy. The insulin‐like growth factor (IGF) system has an established role in mediating the effects of GH on bone and IGF binding proteins (IGFBP)‐4 and IGFBP‐5 have been shown to modulate the effects of IGFs in bone. Therefore, we studied serum levels of IGFBP‐4 and IGFBP‐5 and their relationship to serum levels of bone biochemical markers and BMD in adults with GH deficiency (GHD) before and during GH therapy. Serum levels of IGFBP‐5 and IGFBP‐4 were measured on samples from 20 patients (11 males) 22–57 years of age. All had IGF‐I serum values below –2 standard deviation score. The first 6 months were placebo controlled and all recieved 3 years of active treatment with the mean dose 0.23 ± 0.01 IU/kg/week divided into daily subcutaneous injections. Serum IGFBP‐5 levels in GHD adults were low at baseline and positively related to total body, femoral neck, trochanter, and Ward's triangle BMD (r = 0.471, 0.549, 0.462, and 0.470, respectively, p < 0.05). The mean serum IGFBP‐5 level increased by about 2‐fold within 3 months after the initiation of GH therapy and was correlated with serum IGF‐I (r = 0.719, 0.801, and 0.722 before and after 18 and 36 months, respectively, p < 0.001). A positive correlation between serum IGFBP‐5 levels and lumbar spine BMD was found during GH treatment but not before. The percentage increase of serum IGFBP‐5 after GH therapy showed a positive correlation with the percentage increase of total alkaline phosphate activity (r = 0.347 p < 0.05). In contrast to IGFBP‐5, serum IGFBP‐4 levels were positively related to body mass index (r = 0.607, p < 0.01). Baseline serum IGFBP‐4 levels also correlated with total body, femoral neck, trochanter, and Ward's triangle BMD (r = 0.502, 0.590, 0.612, and 0.471, respectively, p < 0.05). The mean serum IGFBP‐4 level was increased by 25% within 3 months after initiation of GH therapy and did not correlate with serum IGF‐I levels. Although the above findings are consistent with the idea that GH‐induced changes in serum IGFBP‐5 and IGFBP‐4 levels may in part mediate the anabolic effects of GH on bone tissue in adults with GHD, further studies are needed to establish the cause and effect relationship.