Growth hormone (GH) replacement therapy with duration of several years is known to be safe and beneficial in GH-deficient adult patients. However, long-term follow-up data on GH substitution, cognition, and well-being are scarce. The purpose of this study was to investigate whether the benefits of GH replacement in psychological functioning found in previous studies lasting up to 2 years are preserved over a 10-year follow-up period. Twenty-three men (mean age at baseline 28.6 years) with childhood-onset GH deficiency were studied during a 10-year period of GH substitution. Memory tasks, mood questionnaires, and IGF-I values were obtained at baseline and after 0.5, 1, 2, 3, 5, and 10 years of GH substitution. Both mood and memory improved during GH therapy. After 6 months of treatment, anxiety and tension were reduced and vigor had improved. Memory improved after 1 year of substitution. These improvements were maintained during the 10-year follow-up period. Higher intra-subject IGF-I levels were associated with better mood (anxiety, tension, vigor). This study shows that 10 years of GH therapy is beneficial in terms of well-being and cognitive functioning in childhood-onset GH-deficient men. It may be concluded that once the decision to start GH treatment has been taken, this may imply that GH therapy has to be continued for a long period to maintain the psychological improvements and to prevent a relapse.