Since global health-related quality of life (GHRQL) reflects broad impacts of treatment, its assessment in an advanced-stage disease trial should add valuable clinical information beyond that of a targeted symptom. Using latent trajectory modeling that allowed for individual trends as well as overall relationships, we reanalyzed three repeated assessments of the present pain intensity from the McGill Pain Questionnaire and the European Organization for Research and Treatment of Cancer Quality of life Questionnaire- Core 30 (QLQ-C30) GHRQL score from a hormone-refractory prostate cancer trial. Within- and between-treatment differences not detected in the original S9916 report of pain palliation and GHRQL suggested substantial individual variation in GHRQL level and change after controlling for within-assessment pain. The treatment had a differential effect on the relationship between GHRQL and pain; we observed an approximately threefold stronger association of reported pain with GHRQL in the docetaxel plus estramustine (D + E) arm compared with the mitoxantrone plus prednisone (M + P) arm (P = .02). In addition, the treatment had an effect, on average, on the rate of change in GHRQL, after controlling for pain level. GHRQL for patients on the M + P arm tended to improve over the assessment period while GHRQL tended to deteriorate for patients on the D + E arm (P = .02). Important, interpretable effects and systematic individual variation in GHRQL remain after controlling statistically for the effects of pain, the targeted symptom, in this trial. In addition, identifying the rate at which a person's GHRQL changes or responds to treatment provides clinically relevant information.