BACKGROUND: A total of 4 additional splice variants (survivin-DeltaEx3, survivin 2alpha, survivin-2B, and survivin-3B) have been described for survivin [baculoviral IAP repeat-containing protein (BIRC-5), approved gene symbol BIRC5], which has been implicated in both inhibition of apoptosis and regulation in mitosis in many tumor types. In this study, we assessed whether the survivin splice variants modulate or add to the prognostic value of total survivin in breast cancer. METHODS: With quantitative reverse transcription-PCR, we measured mRNA concentrations of survivin and all variants in tumor tissue from 275 patients with breast cancer and associated these with clinicopathologic characteristics and relapse-free survival. RESULTS: Total survivin, survivin-DeltaEx3, and survivin 2alpha mRNA levels were associated with young age and ductal histology. Total survivin and survivin-DeltaEx3 were highest in samples with advanced histological grade, whereas patients with 4-9 involved lymph nodes expressed less survivin-2B mRNA than those with 1-3 involved nodes. All variants were higher in tumors negative for steroid hormone receptors. Total survivin, survivin 2alpha, and survivin-3B were associated with poor relapse-free survival in univariate analyses. Survivin 2alpha and survivin-3B added to the prognostic value of total survivin in multivariate analyses. In addition, the prognostic value of total survivin was evident only in the presence of higher expression levels of these 2 variants. CONCLUSIONS: All variants of survivin exhibited particular associations with clinicopathologic characteristics (age, histology, grade, and steroid hormone receptor status) of breast cancer patients. Survival analyses suggest a modulating role of survivin 2alpha and survivin-3B on the biological function of total survivin.