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Background: Greater than 90% of dogs with appendicular osteosarcoma will develop pulmonary metastasis despite the standard of care. Available treatments have limited efficacy for stage III disease. Zoledronate, a bisphosphonate, induces apoptosis of canine osteosarcoma cells and appears to modulate the tumour microenvironment., Objectives: This prospective, single institutional phase IIa trial investigated the use of single agent zoledronate in dogs with pulmonary metastases from osteosarcoma., Methods: Zoledronate was administered once monthly, and thoracic radiographs were used to assess response., Results: Eleven dogs were enrolled. Stable disease was achieved in two of eight dogs available for response assessment. The median progression-free survival was 28 days (range: 4-93 days). The median stage III-specific survival time was 92 days. Adverse events were reported in four dogs; two dogs developed grade III or higher toxicities. Notable adverse events included conjunctivitis, fever, hypocalcaemia, and hypophosphatemia., Conclusions: Zoledronate appears to have limited efficacy as a single agent for stage III osteosarcoma and may be associated with unexpected toxicity in this population. This clinical trial was registered on the AVMA Animal Health Studies Database (AAHSD004396)., (© 2022 The Authors. Veterinary Medicine and Science published by John Wiley & Sons Ltd.)