BACKGROUND: Intermittent dosing may reduce the adverse events (AEs) of androgen-deprivation therapy (ADT). OBJECTIVE: To compare intermittent androgen deprivation (IAD) and continuous androgen deprivation (CAD) with regard to health-related quality of life (QoL). DESIGN, SETTING, AND PARTICIPANTS: A total of 852 men with advanced prostate cancer (PCa) were enrolled to receive goserelin acetate 3.6mg every 28 d for 24 wk. A total of 554 patients whose prostate-specific antigen (PSA) decreased to <10 ng/ml or by ≥50% (<20 ng/ml at baseline) were randomised to IAD or CAD. INTERVENTION: In the IAD arm, ADT was resumed for at least 24 wk whenever PSA increased >20 ng/ml or above baseline. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: QoL was monitored with a validated Cleary 30-item questionnaire and analysed by the Mann-Whitney U test, 0.5 standard deviation rule, and repeated measures analysis of variance. AEs and adverse drug reactions (ADRs) were analysed by the chi-square test. RESULTS AND LIMITATIONS: Median follow-up was 65 mo. Significant differences in QoL emerged in activity limitation, physical capacity, and sexual functioning, favouring IAD. No significant differences emerged in the prevalence of AEs: 87 patients in the IAD arm (31.8%) and 95 in the CAD arm (33.9%) had cardiovascular (CV) AEs (p=0.59), with 25 (9.1%) and 29 (10.4%) withdrawn (p=0.62), and 21 (7.7%) and 24 (8.6%) dying because of a CV event (p=0.70), respectively; bone fractures occurred in 19 (6.9%) and 15 (5.4%) patients (p=0.44), respectively. Hot flushes or night sweats were the most common ADRs (47.1% vs 50.4%; p=0.44). Erectile dysfunction (15.7% vs 7.9%; p=0.042) and depressed mood (2.2 vs 0%; p=0.032) were more common in the IAD arm. CONCLUSIONS: IAD showed benefits in the treatment of advanced PCa with respect to QoL. The prevalence of AEs was not significantly lower with IAD. TRIAL REGISTRATION: ClinicalTrials.gov, NCT00293670.