Cyclin D1 is a key cell cycle regulatory protein with demonstrated oncogenic activity in a variety of malignancies. Cyclin D1 mRNA and protein are overexpressed in approximately 50% of primary breast carcinomas; however, the pathophysiological consequences of increased expression remain unclear. To investigate the functional sequelae of cyclin D1 mRNA overexpression, we analyzed clinical outcome in relation to the cyclin D1 mRNA level in 253 primary breast cancer patients (median follow-up, 75 months) with particular reference to estrogen receptor (ER) status and endocrine response. Overall, with the exception of the relationship between cyclin D1 mRNA expression and the ER, cyclin D1 mRNA was not associated with other clinicopathological features such as age, menopausal status, axillary lymph node status, vascular invasion, tumor size, type, and grade. However, in patients with ER-positive tumors (n = 182), high levels of cyclin D1 mRNA were associated with increased risk of relapse (P = 0.0016), local recurrence (P = 0.025), metastasis (P = 0.019), and death (P = 0.025). In contrast, there were no clinical correlations with cyclin D1 expression in ER-negative disease (n = 71). In 33 patients who received endocrine therapy for their primary or recurrent breast cancers, there was an apparent association between a high cyclin D1 mRNA level and a shorter response duration within the ER-positive subgroup (P = 0.04). Our findings indicate that overexpression of cyclin D1 mRNA correlates with a worse prognosis within the ER-positive breast cancer phenotype and may be a contributing factor to the development of endocrine resistance in ER-positive disease.