Objective Few studies have determined the effects of long-term growth hormone (GH) replacement on quality of life (QoL). This study investigated the effects of 7 years of GH replacement on QoL. Design A prospective, single-center, open-label study of 95 adults (mean age 52.8 years; 46 men) with adult-onset GH deficiency (GHD). Methods QoL was measured using Quality of Life-Assessment for Growth Hormone Deficiency in Adults (QoL-AGHDA) and Psychological General Well-Being (PGWB) scores. Results The GH dose was gradually increased from 0.13 mg/day to 0.42 mg/day. IGF-I SD score increased from −1.49 at baseline to 0.35 at study end. The GH replacement induced sustained improvements in total QoL-AGHDA and PGWB scores. GHD women had a more marked improvement in total QoL-AGHDA score than GHD men after 5 and 7 years. Most of the improvement in QoL was seen during the first year, but there was a small further improvement also after one year as measured using QoL-AGHDA. All QoL-AGHDA dimensions improved, but the improvement in memory and concentration as well as tenseness occurred later than that of other dimensions. Correlation analysis demonstrated that the patients with the lowest baseline QoL had the greatest improvement in QoL. Conclusions Seven years of GH replacement improved QoL with the most marked improvements in GHD women and in patients with low baseline QoL. Most, but not all, of the improvement in QoL was seen during the first year. Some QoL-AGHDA dimensions (memory and concentration, tenseness) responded at a slower rate than other dimensions.