Previous in vitro studies have implied that the Wnt-5a gene plays a role as a tumor suppressor. To explore the clinical relevance of this concept, 96 primary invasive breast carcinomas were stained with a novel anti-Wnt-5a antibody. Loss of Wnt-5a protein expression, evident in 44% of the invasive ductal carcinomas (n = 59), was significantly associated with higher histological grade (P = 0.01) and absence of estrogen (P = 0.003) and progesterone (P = 0.02) receptors. By contrast, loss of Wnt-5a protein in 24% of the invasive lobular carcinomas (n = 37) was not significantly related to any of the variables we investigated. The prognostic value of Wnt-5a for metastatic potential was evaluated by analyzing 83 additional invasive primary ductal carcinomas from patients with a longer follow-up time. We found that Wnt-5a expression was lost in tumors from 78% of the patients with recurrent disease (n = 32) compared with 35% of the recurrence-free patients (n = 51; P < 0.001), and that recurrence-free survival was significantly shorter in the Wnt-5a-negative group (P < 0.001). In multivariate analyses, loss of Wnt-5a expression proved to be an independent and powerful predictor of recurrence after adjustment for lymph node status and tumor size (hazard ratio = 4.8; P = 0.002). Our results show that loss of Wnt-5a increases the risk of early relapse and death because of recurrent ductal breast cancer, findings that support the notion that this protein retains tumor suppressor function by virtue of its effects on cell adhesion and motility.