Background: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a key player in the extrinsic pathway of apoptosis; it selectively damages cancer cells through binding to its surface receptors, however, cancers can escape this pathway through expression of dysfunctional decoy receptors. Purpose: The present study directed mainly to elucidate the serum TRAIL levels in breast cancer patients and to explore the variation in gene expression of TRAIL death and decoy receptors in breast cancer tissues, and to explore their role as prognostic markers in breast cancer as well as to detect their correlation with Patients' Clinical Characteristics. Subjects and Methods: TRAIL levels were assayed in the sera of 124 breast cancer patients and 150 healthy females. Moreover, the expression of TRAIL death and decoy receptors was determined in both malignant and adjacent normal breast tissues collected from patients. ER, PR and Her-2 expression in breast cancer tissue were performed using immunohistochemical method. Apoptotic index (AI) was analyzed using H&E stain under light microscopy. Results: Serum levels of TRAIL in breast cancer patients were significantly lower than controls (P < 0.001), additionally, the expression of DR4, DR5 and DcR1 were significantly up-regulated (p < 0.001, p < 0.001, p = 0.039, respectively), however, no significant difference was found in the expression of DcR2 in breast cancer tissues as compared to the corresponding normal tissues. Moreover, the apoptotic index in breast cancer tissues was significantly higher than the corresponding normal tissues. On the other side, decreased Serum TRAIL levels and increased DcR1 expression were associated with decreased overall patients' survival. Conclusions: The expression of both DR4 and DR5 is required for TRAILinduced apoptosis in breast cancer tissues; in addition, serum TRAIL and pro-How to cite this paper: Ibrahim