The present study evaluates the effects of one year of discontinuation and one year of growth hormone (GH) treatment on quality of life (QoL) in young adults with childhood-onset growth hormone deficiency (CO-GHD). Twenty-two subjects (14 males, 8 females; 11 isolated growth hormone deficient [IGHD], 11 multiple pituitary hormone deficient [MPHD]), aged between 15 and 22 years, on ongoing GH treatment were assessed during one year of discontinuation. Thereafter, 9 of these patients, who were found to be still GH deficient (GHD), added by 11 newly recruited GHD patients who also were not treated in the preceding year (in total 10 males and 10 females, aged between 17 and 27, 5 IGHD, 15 MPHD), restarted GH treatment for one year. During discontinuation and restart of GH treatment somatic and psychological assessments took place every 6 months. In the first 6 months of the GH discontinuation period insulin-like growth factor I (IGF-I) level significantly declined whereas no further decrease in IGF-I was seen after month 6. The number of psychological complaints and depression increased only during the first 6 months of discontinuation. Across the 12-month of discontinuation tension increased in MPHD and decreased in IGHD patients. Only in the first 6 months of GH treatment IGF-I level increased, anxiety decreased and QoL improved. Depression scores tended to decrease across the 12 month treatment period. During the 2-year discontinuation and treatment period intra-subject IGF-I level was negatively correlated with depression, fatigue, tension and anxiety and positively with vigor and memory. At the end of the treatment period all psychometric parameters were similar or even improved compared to those at the start of the discontinuation period. It is concluded that one year discontinuation of GH treatment leads to a decrease in QoL within 6 months which effect is counteracted within 6 months after restart of GH treatment.