Increased numbers of tumor-associated macrophages correlate with rapid tumor growth and metastasis in tumors. Thus, macrophage depletion has potential as a novel cancer therapy and positive responses have been reported in rodent tumor models. To investigate the effectiveness of this approach in dogs with cancer, we evaluated the effects of the macrophage depleting agent liposomal clodronate (LC) in dogs with soft tissue sarcoma (STS). To this end, we conducted a clinical trial of LC therapy in thirteen dogs with soft tissue sarcoma. Repeated LC administration was well tolerated clinically. Preliminary examination of tumor biopsy sets from 5 of the 13 dogs demonstrated that the density of CD11b⁺ macrophages was significantly decreased after LC treatment. Circulating concentrations of IL-8 were also significantly reduced. These preliminary studies are the first to suggest that LC can be used as a systemic macrophage-depleting agent in dogs to reduce numbers of tumor-associated macrophages.