Background: Although the beneficial effect of growth hormone replacement on QoL in adults with GHD is well recognized, the long-term effect of this therapy on QoL remains uncertain. OBJECTIVES: To determine the effect of long term GH replacement on QoL in patients compared with country-specific normative data for the general population (GP). METHODS: QoL was measured using Quality of Life Assessment for Growth Hormone Deficiency in Adults (QoL-AGHDA) in patients and GP in Sweden and England & Wales (E&W). QoL-AGHDA is a 25-item questionnaire that elicits yes/no responses that are used to compute a summary score. GP data were obtained from 1,682 randomly selected individuals from Sweden and 892 from E&W. These data were compared with KIMS (Pfizer International Metabolic Database) data for 121 patients from Sweden and 77 from E&W with 5 years of complete follow-up. Age-range was 20-79 years. Linear regression methods were used to estimate age- and gender-adjusted differences between patients and the GP at one-year intervals. The significance level was set at 5%. RESULTS: The (adjusted to age 50) mean QoL-AGHDA score at baseline were 8.21 and 15.2 (SEM 0.44 and 0.68) for the Swedish and E&W patients, respectively. For the GP samples the corresponding mean scores were 3.80 and 6.6 (SEM 0.12 and 0.20). The mean difference between patient scores at baseline and GP scores were -4.4 for Sweden and -8.6 for E&W (p<0.0001). However, these differences reduced markedly over the first year of treatment and were subsequently maintained at statistically non-significant differences compared to the general populations. CONCLUSION: This study shows that adults with GHD who receive long-term GH replacement benefit most with respect to QoL during the first 12 months of therapy and that this improvement was maintained at levels close to normalization in QoL over 5 years of follow up.