In previous studies, the gene expression profiles of two hamster pancreatic cancer cells with different potentials for invasion and metastasis were analyzed. In the present study, we identified that one of the genes expressed strongly in the highly metastatic cell line is hamster oxysterol binding protein-related protein (ORP)-5. The aim of the present study was to clarify the relationship between ORP5 and invasion and poor prognosis of human pancreatic cancer. Invasion assays were carried out in both hamster and human pancreatic cancer cells by suppressing the ORP5 gene with short interfering RNA or inducing its expression by introducing an expression vector. To evaluate the relationship between ORP5 and the characteristics of human pancreatic cancer, 56 pancreatic cancer tissue specimens were analyzed and the ORP5 expression in each pancreatic cancer tissue specimen was analyzed by immunohistochemistry. In both the hamster and human pancreatic cancer cells, suppression of ORP5 significantly reduced the invasion rate of the cells and induction of ORP5 significantly enhanced the invasion rate of the cells. In the clinical sample, the median survival times of the patients with ORP5-positive (n = 33) and ORP5-negative (n = 23) cancer were 8.3 and 17.2 months, respectively (P = 0.02). Also, the 1-year survival rates of patients with ORP5-positive and ORP5-negative cancer were 36.4 and 73.9%, respectively (P = 0.005). The ORP5 expression level was related to both invasion and poor prognosis in human pancreatic cancer. These findings suggest that the expression of ORP5 may induce cancer cell invasion, resulting in the poor prognosis of pancreatic cancer.