Breast cancer is the most common cancer in women. The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) pathway transmits apoptotic signals. Novel anticancer agents that activate this system are in clinical development, including anti-breast cancer.The tissue microarray technique was applied. We used an array of breast cancer tissues from a large group of patients (>800) to assess the protein expression of TRAIL-R1, TRAIL-R2, the long isoform of FLICE-inhibitory protein and total FLICE-inhibitory protein (FLIP(L) and FLIP(T)). Disease-free survival was examined by Kaplan-Meier estimates and the log-rank test. The independence of prognostic factors was determined by Cox multivariate analysis.High intra-tumoral expression of all these proteins of the TRAIL pathway was found. The TRAIL receptors and FLIP(L) were not associated with survival. On univariate analysis, strong FLIP(T) expression was associated with a significantly better survival (p = 0.001). On multivariate analysis using the Cox proportional hazards model, FLIP(T) phenotype was significantly associated with a good prognosis in this series (HR 0.52, 95 % CI 0.35-0.78, p = 0.039). Results indicate that this association is valid for all the biological subtypes of breast cancer. The expression of FLIP(T) was especially high in the luminal subtype, known for its good prognosis.These findings support the use of agonistic TRAIL antibodies and drugs targeting FLIP in breast cancer patients. Over-expression of FLIP(T) but not TRAIL-R1, TRAIL-R2 or FLIP(L) provides stage-independent prognostic information in breast cancer patients. This indicates a clinically less aggressive phenotype.