The discoidin domain receptors, DDR1 and DDR2, have been linked with numerous human cancers. We sought to determine expression level and distribution of DDRs in human breast cancer, and investigate prognostic determinates to determine whether levels of DDRs could predict survival. Tumor samples from 122 breast cancer patients were analyzed for relative expression of DDRs. An additional 24 matched tumor and normal tissues were tested for differential expression of DDR1 and DDR2. DDR2 was found to be significantly increased by 6-fold (P = 0.0005) and DDR1 decreased (P = 0.0001) in tumor vs. normal breast tissue. DDR1 expression was not predictive for patient survival; however, DDR2 expression was significantly associated with disease-free (HR = 0.55, 95 % CI = 0.24-0.78, P = 0.026) and overall survival (HR = 0.46, 95 % CI = 0.35-0.84, P = 0.019). Multivariate analysis revealed DDR2 is an independent favorable predictor for prognosis independent of tumor stage, histology, and patient age. The present research provided the first evidence that increased DDR2 mRNA expression in primary human breast cancer might be a powerful, independent predictor of recurrence and outcome.