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Skeletal complications of cancer decrease health-related quality of life. Bisphosphonates can prevent skeletal-related events. We collected resource use data prospectively for 930 patients alongside a multinational trial of zoledronic acid versus pamidronate for patients with metastatic multiple myeloma or breast cancer and ≥1 bone lesion. Country-specific unit costs were assigned to counts of resource use from randomization through last trial visit. Total costs were calculated by summing costs for medical resources, plus costs of institutional care and study medications and administration. Resource use was similar for both groups. Approximately half of the patients were hospitalized at least once during the mean follow-up of 10 months (52.8% for zoledronic acid versus 52.6% for pamidronate; P = 0.9504). The average number of hospital days was 8.9 for zoledronic acid versus 9.2 for pamidronate (P = 0.728). The mean total cost was $16,434 for zoledronic acid and $15,735 for pamidronate, an incremental cost of $699 (95% confidence interval [CI], −1047 to 2163). Mean total costs for patients with multiple myeloma were $1982 (95% CI, −1491 to 5335) higher for zoledronic acid ($17,958) than for pamidronate ($15,976). However, among patients with breast cancer, total costs in both groups were approximately equal ($15,703 for zoledronic acid versus $15,680 for pamidronate; 95% CI for the difference: −1875 to 2012). There were no significant cost differences between patients receiving zoledronic acid and those receiving pamidronate.