Prostatic carcinoma and its treatment have been associated with adverse effects on health-related quality of life (HRQoL). Individual differences in appraisal and coping have been suggested to mediate these HRQoL outcomes. A randomized trial of 65 men with non-localized prostate cancer compared several treatments and tested associations between appraisal, coping, and HRQoL. These patients, and 16 community volunteers matched for age and general health, undertook psychosocial assessments before treatment and after 6 months of treatment. Compared with baseline assessments, men on hormonal treatments reported impaired sexual function. Groups did not differ on emotional distress, existential satisfaction, subjective cognitive function, physical symptoms, or social and role functioning. For individuals, hormonal treatments were more frequently associated with decreased sexual, social and role functioning, but were also associated with improved physical symptoms. In hierarchical regression analysis, HRQoL was lower for men who had more comorbid illnesses, a history of neurological dysfunction, higher threat appraisals, or higher use of coping strategies at baseline. These results showed that pharmacological hormonal ablation for prostate cancer can improve or decrease HRQoL in different domains. HRQoL in men with prostate cancer was associated more strongly with appraisal and coping than with medical variables.