Breast carcinomas have been reported to contain a subpopulation of CD44+/CD24- tumor cells with stem cell-like properties. This study investigates the significance of these two molecules in connection with tumor aggression and prognosis. The phenotypic profile of 139 breast carcinomas was investigated in paraffin sections using markers previously associated with stem cell-like properties (CD44, CD24), the "triple-state" (ER, PR, c-erb-B2), and angiogenesis (CD31). Tumors with >10% of CD44 and CD24 cancer cells were considered positive. The prevalence of CD44+ and CD24+ breast carcinomas in the series was 51.8% and 41.7%, respectively. Patients with the CD44(+)/CD24(-) phenotype had a 10-year lower median age at presentation and harbored tumors with a triple-negative state. They experienced an unfavorable prognosis. Lack of CD44 expression was associated with lymph node involvement, regardless of CD24 status, whereas the lack of both CD44 and CD24 was connected with high histologic grade and unfavorable prognosis which, notably, was the worse among all phenotypes. In multivariate analysis, the CD44(-)/CD24(-) phenotype, the nodal involvement, the vascular density and the ER-/PR-/c-erbB-2-profile were independent prognostic variables. It is concluded that assessment of the CD44/CD24 status may reveal distinct subgroups of breast cancer patients with different clinical behavior. The unsatisfactory response of the triple-negative tumors to current chemotherapy and their intimate link with the CD44(+)/CD24(-) phenotype, makes CD44 targeting an attractive therapeutic alternative for breast cancer patients. The strong association between the CD44(-)/CD24(-) phenotype and prognosis requires further investigation.