This study prospectively evaluated quality of life (QOL) in localized prostate cancer patients undergoing radiotherapy, and it examined the relationships between QOL, depression, fatigue, and sleep disturbance. Instruments that were used are Functional Assessment of Cancer Therapy for Prostate (FACT-P), Beck Depression Inventory (BDI), Piper Fatigue Scale (PFS), and Epworth Sleepiness Scale (ESS). We evaluated patients at preradiotherapy (PRT), midway radiotherapy (MRT), completion of radiotherapy (CRT), follow-up radiotherapy (4 to 8 wk) (FRT), and long-term follow-up radiotherapy (FRT2) (12 mo or more). Forty participants with a mean age of 67.8 yr were studied. Duration of radiotherapy was 7-8 wk. Mean long-term follow-up period post-CRT was 16.2 mo (range 12- 24 mo). All patients had clinical T1c to T2b prostate cancer. Prostate Cancer Specific (PCS) and Physical Well-Being (PWB) subscales of FACT-P, scores at MRT and CRT were significantly lower than at PRT. At FRT2, PWB scores declined further, while PCS scores increased. PFS median scores were significantly higher at CRT and at FRT2 as compared with PRT. Patients scoring higher on PFS were more likely to report a poorer QOL and PWB as measured with FACT-P questionnaire. No significant changes were noted in the BDI and ESS scores during the study periods. The PWB declined during and at CRT and worsened at FRT2. Decline in PCS subscale scores during and at CRT reflects worsening of urinary symptoms and appearance of bowel problems. The scores improved at long-term follow-up. A relationship was found to exist between physical well-being and fatigue.