<i>Background/Aims:</i> Decreased GH and IGF-I levels and increased GH responsiveness are frequently reported in obesity. As GH-deficient adults are commonly obese, the role of obesity in affecting hepatic responsiveness of IGF-I generation to GH stimulation is unclear in severe GH-deficient states. To address this question, we challenged a cohort of severely GH-deficient non-obese and obese adults with a <i>fixed</i> low GH dose (0.2 mg/day), and examined the relationship of body mass index (BMI) with IGF-I response. <i>Methods:</i> 12 non-obese (6 males, median BMI 24.7 kg/m²) and 14 obese (7 males, median BMI 45.2 kg/m²) adults with severe GH deficiency were studied for 8 weeks. Blood samples were collected at baseline, and weeks 4 and 8. <i>Results:</i> There was a larger increment and reduced variability of IGF-I levels in obese compared to non-obese GH-deficient adults at week 8, but not at week 4. A similar but smaller increment and less variability was observed with IGFBP-3. Increment IGF-I positively correlated with baseline BMI at weeks 4 (r = 0.49, p < 0.02) and 8 (r = 0.47, p < 0.02). No gender differences were observed with the IGF-I and IGFBP-3 response. <i>Conclusions:</i> This study demonstrates that there is a larger increment and deceased individual variability of IGF-I to the low GH replacement dose in obese compared to non-obese adults with severe GH deficiency, regardless of gender. The positive association of IGF-I increment with BMI implies a greater impact of obesity rather than GH deficiency in enhancing hepatic sensitivity to GH. These findings, thus, question the reliability of interpreting single serum IGF-I levels in non-obese adults with severe GH deficiency treated with low GH replacement doses.