BACKGROUND/AIMS: It is unknown whether long-term growth hormone replacement therapy (GHRT) affects body composition in an age- or sex-dependent manner. We aimed to study the effects of 4 years of GHRT on body composition in a large cohort of patients with hypopituitarism compared to a reference population matched by age and sex. METHODS: A total of 964 GH-deficient adults from KIMS (Pfizer International Metabolic Database) with adult-onset hypopituitarism, adequately replaced with all pituitary hormones except for GH at baseline were included. A random sample of the general population (2,301 subjects) from a similar time period was used as reference. Patients and controls were grouped by sex in 5 age cohorts of 10 years. Main outcome measures were changes in BMI and waist circumference after 4 years of GHRT. RESULTS: In younger patients (28-47 years), 4 years of GHRT resulted in a BMI increase similar to that observed in the reference population, but older patients (48-67 years) had significantly less BMI increase than age-matched healthy controls. Significant differences were seen in waist circumference in patients of all age cohorts who showed virtually no change after 4 years of GHRT compared to approximately 4 cm of increase in the reference population. CONCLUSION: Four years of GHRT resulted in improvements in BMI and waist circumference in patients with adult-onset hypopituitarism compared to age-matched controls observed during the same follow-up time. Despite these beneficial effects on body composition, BMI and waist circumference remained higher in patients on GHRT compared to healthy controls.