It has been suggested that the cAMP responsive element-binding protein (CREB) may act as a transcription regulator of aromatase in breast cancer cells. However, there is little knowledge on the expression of CREB1 in human breast cancer and its clinical significance. The current study investigated the expression pattern of CREB1 in human breast cancer at the mRNA and protein level and correlated it with the clinical outcome. CREB1 staining was primarily seen in the nucleus of both normal and tumour cells. At the mRNA level, we found a significantly higher level of CREB1 in breast tumour tissues (n=120) as compared to non-neoplastic mammary tissues (n=33, p=0.0092). When compared between different histological types CREB1 expression was significantly higher in ductal carcinoma as compared to lobular and other breast carcinoma. Patients with a poor prognosis and with metastasis had a markedly raised level of CREB1 compared to patients who were disease free. In addition, node-positive tumours had higher levels of CREB1 than node-negative tumours (p=0.0018). Finally, patients with high levels of CREB1 had a significantly shorter disease-free survival [95.3 (68.4-122.3, 95% CI) months] compared with those with lower levels [133.9 (123.5-144.2) months, p=0.0193]. This study demonstrates that the level of CREB1 in breast cancer patients is elevated and is significantly raised in patients with a poor prognosis, metastatic disease and nodal involvement. We conclude that the level of CREB1 expression is aberrant in human breast cancer and is associated with disease progression in breast cancer patients.