Intravenous zoledronic acid (ZOL) is an integral component for the management of patients with bone metastases, but can be associated with transient flu-like symptoms, which generally occur only with the first infusion and are typically manageable with nonprescription analgesics. A 50-year-old woman with a bone metastasis secondary to breast cancer received radiation therapy, brand-name ZOL (Zometa®), and letrozole. During the first 3 cycles of Zometa (4 mg every 3–4 weeks), no acute adverse events were reported. For the next 2 cycles she was switched to generic ZOL and experienced severe toxicity (nausea, vomiting, extreme weakness, and incapacitating bone pain) that required hospitalization. Toxicity differences between generic ZOL and Zometa led the patient to pay additional costs for Zometa, and subsequent Zometa infusions were without incident. This is the first case report documenting a clinically significant difference between the safety profiles of a generic formulation of ZOL and brand-name Zometa.