CD73, an ecto‐enzyme overexpressed in breast‐cancer cells, catalyzes the dephosphorylation of adenosine monophosphates into adenosine. Anti‐CD73 slows breast cancer growth and its spread both in vivo and in vitro. In this study, we investigated the relation of CD73 to epidermal growth factor receptor (EGFR) expression using tissue array and breast cancer cell lines. We found that CD73 expression correlated positively to EGFR expression in vivo (n = 80, r = 0.425, P < 0.01) and in vitro. EGFR expression can be decreased by suppressing CD73 with an inhibitor or small shRNA, and this effect was reversed by adenosine and NECA (adenosine A2 receptor agonist), which suggested that adenosine is involved in EGFR expression regulated by CD73 (P < 0.01). We also showed that CD73 regulates EGFR phosphorylation by Src (P < 0.01). By transcription factor (TF) assay, CD73 was found to regulate some associated TFs activity such as PPARγ, which mediates EGFR expression, although whether PPARγ mediates the effect of CD73 on EGFR expression needs further study. The Kaplan–Meier recurrence‐free survival curves for CD73 were also plotted in www.kmplot.com. The curves show that CD73 expression separates the cases into significantly different prognostic groups among the estrogen receptor‐negative cancers (P < 0.01). Our results suggest that CD73 may be a potential prognostic biomarker associated with coexpression of EGFR in human breast cancer. © 2012 IUBMB. IUBMB Life, 64(11): 911–920, 2012