BACKGROUND: Research on individual differences in health-related quality of life (HRQOL) can identify intervention targets and important covariates in analyses of treatment outcomes. OBJECTIVES: The objectives of this study were to describe HRQOL trajectories for women with metastatic breast cancer in a randomized trial of bisphosphonates and to identify characteristics associated with variations in HRQOL. RESEARCH DESIGN: We conducted a prospective quality-of-life study within a randomized, controlled trial. SUBJECTS: We studied women with metastatic breast cancer receiving zoledronic acid or pamidronate disodium to reduce the incidence of skeletal-related events (SREs). MAIN OUTCOME MEASURES: HRQOL was measured at fixed time points during the trial. Individual growth-curve modeling was used to describe longitudinal trajectories and to identify predictors of trajectories. RESULTS: For most domains of HRQOL, the mean trajectory reflected a mild increase, which leveled off later in the trial. Older age and full-time employment were associated with higher baseline HRQOL. Longer time from cancer diagnosis to randomization, lower Eastern Cooperative Oncology Group (ECOG) status (score of 2 ["inactive"]), and a history of SREs were associated with lower baseline HRQOL. Significant differences across geographic regions were observed for all domains. Active ECOG status (score of 0-1) at baseline was predictive of greater increases in all domains of HRQOL except Social/Family Well-Being. Age, geographic region, and time from first bone metastases to randomization were associated with longitudinal changes in some domains. CONCLUSIONS: Women with metastatic breast cancer receiving bisphosphonates for prevention of SREs experienced an overall increase in HRQOL. Variations among women's experiences are explained partly by such characteristics as a history of SREs.