The role of human prolactin and its receptor, the prolactin receptor, in colorectal cancer is largely unknown. Our study aimed to assess the prevalence of prolactin receptor expression, its association with clinicopathological variables, as well as its prognostic value, comparing results of primary tissues with those of corresponding metastases. In all, 373 primary colorectal cancer and 171 corresponding metastases were evaluated for prolactin receptor expression by immunohistochemistry using a tissue microarray technique. Immunoreactivity was semiquantitatively scored as either focal (<10% of tumor cells positive), moderate (10-50%), or extensive (>50%). Prolactin receptor expression was related to clinicopathological parameters as well as patient outcome. To substantiate our findings, prolactin receptor expression was additionally assessed in HT-29 and SW-480 colorectal cancer cell lines using western blot. Prolactin receptor expression was observed in 360 out of 373 (97%) primary tumors, with 21 (6%) cases showing focal, 55 (15%) moderate, and 284 (76%) extensive expression, respectively. Extensive prolactin receptor expression was significantly associated with tumor size (P=0.002) and grade (P<0.001) as well as histological subtype (P<0.001). Somer's D coefficients for concordance of primary tumors with corresponding lymph node and distant metastases were D=0.719 (P<0.001) and D=0.535 (P=0.001), respectively. Extensive prolactin receptor expression was significantly associated with disease progression (P=0.03) and cancer-specific survival (P=0.04) in patients with high-grade cancers. In conclusion, prolactin receptor expression is common in colorectal cancer, with high concordance between primary tumors and corresponding metastases. In view of evolving targeted therapy concepts in colorectal cancer, widespread prolactin receptor expression may offer a therapeutic perspective in affected patients.