Background: Tumor budding (TB) is an important prognostic factor in colorectal carcinoma (CRC). Osteopontin (OPN) functions in various processes such as immune response, migration and invasion, angiogenesis, epithelial–mesenchymal transition (EMT) and metastasis. However, the involvement of OPN and CD44v6, which is a receptor for OPN, in TB has not been clarified. Therefore, we examined the relationship of OPN with TB in CRC and compared the clinicopathological features. Methods: We investigated the expression of OPN and CD44v6 in 83 cases of CRC by immunostaining and analyzed the clinicopathological features.Results: OPN expression was observed only in the cytoplasm of stromal cells such as macrophages and fibroblasts, and not cancer cells. There was a significant correlation between OPN positivity and the degree of differentiation at the invasive front and TB grade. CD44v6 was positive in cancer cells in 72 cases (86.7%) and negative in 11 cases (13.3%). A statistically significant effect on overall survival (OS) was identified between the OPN-positive group [median OS: 1586 (range, 30–2749) days] and the OPN-negative group [median OS: 1901 (range, 8–2665) days] (log-rank test, p=0.011).Conclusions: OPN analysis may reveal factors that influence prognosis.