The ectonucleotidase CD73 degrades adenosine triphosphate (ATP) to adenosine which potently inhibits host immune responses against cancer. This study investigated the expression level and prognostic significance of CD73 in human rectal adenocarcinoma. Our data demonstrated that CD73 staining strongly marked both malignant epithelial cells and stromal components where the protein and messenger RNA (mRNA) expression levels of CD73 were significantly increased compared with paracancerous controls. High CD73 expression in tumor cells can be used as an independent factor for predicting poor patients' prognosis; however, patients with higher density of stromal CD73 were more likely to have favorable characteristics (early T and tumor-node-metastasis (TNM) stages) and overall survival. Notably, combined CD73 expression analysis in both tumoral and stromal compartments was more efficient to foretell patient's outcome where patients with increased CD73 in tumor cells but decreased CD73 in stroma displayed a worst prognosis. Taken together, the current study revealed CD73 expression was increased in both tumoral and stromal compartments. Although upregulated CD73 expression in tumor cells correlates with a poor prognosis in patients with rectal adenocarcinoma, the combination of CD73 expression in malignant epithelial cells and tumor stroma may have a better prognostic value.