Although significant progress has been made in the treatment of childhood acute lymphoblastic leukemia (ALL) the prognosis following relapse is still poor. Additional prognostic indicators are needed to better target treatment and thereby improve the treatment of these patients. We have previously demonstrated an association between poor outcome and CD44v6 expression in a heterogeneous cohort of patients. Others have shown by microarray analysis that CD44 expression in diagnostic samples is linked with relapse risk. In this study, we examined CD44 and CD44v6 protein expression by flow cytometry and CD44v6 mRNA expression by quantitative RT-PCR in diagnostic samples from 97 pediatric patients with ALL. We found that CD44 protein expression was associated with disease relapse and was independent of age and WCC. In contrast, high CD44v6 expression was not associated with relapse. These findings may assist in the process of refining prognostic groups for children with ALL.