Background <p>Multinucleated giant cells are commonly observed in various malignancies; however their clinical and biological significance remains largely unexplored and it has been hypothesised that the cells may play a role in vascular mimicry, tumour progression and tumour survival. This study aimed to investigate the expression of smooth muscle actin and CD31 in feline post-injection site fibrosarcomas, focusing on relationships between multinucleated giant cells presence, tumour grade, and vascular density to elucidate their potential role in tumour progression.</p> Results <p>A total of 61 feline post-injection site fibrosarcomas, histologically graded into grades I, II, and III, were examined immunohistochemically. Smooth muscle actin immunoreactivity was detected in 57/61 (93.4%) cases. Multinucleated giant cells expressing CD31 were identified in 39/61 (63.9%) cases, predominantly in high-grade tumours, with a correlation observed between multinucleated giant cell presence, tumour grade, and mitotic index. Vascular density differed across tumour grades. A negative correlation between vascular density, tumour grade and necrosis score was identified. Additionally, a negative correlation was observed between multinucleated giant cells presence and vascular density.</p> Conclusions <p>The findings suggest a complex tumour microenvironment in which multinucleated giant cells and vascular mimicry may facilitate tumour survival under hypoxic conditions, potentially contributing to an aggressive tumour phenotype.</p>