Background: Cancer is a heterogeneous disease encompassing various subtypes. Exploration of novel biomarkers is important to tailor therapy. Aim: The main aim of this study was toexplore the prognostic value of soluble CD44 in the sera of breast cancer patients (BCPs), and to correlate its levels with hyaluronic acid (HA), VEGF and p53 levels. Subjects and Methods: Fifty female BCPs were enrolled in the study as a patient group and 50 healthy females as a control group. Cancerous and neighboring normal breast tissues were collected from BCPs. Blood samples were collected from BCPs at diagnosis and control group. CD44 tissue expression was evaluated by immunohistochemistry (IHC). Serum levels of sCD44, HA, VEGF, and p53levels were measured by ELISA. Results: CD44 showed high expression in cancerous breast tissues as compared to control tissues. Circulating sCD44 was highly increased in BCPs and was associated significantly with the expression levels of CD44 in tissues. Serum HA and VEGF levels were highly elevated in BCPs along with the increase in CD44 positivity. In contrast, the decrease in p53 level was associated with higher CD44 expression in BCPs. According to Kaplan-Meier curves, BCPs who expressed high levels of  sCD44 or tissue CD44 showed shorter DFS time than CD44 negative. Conclusion: Tissue and soluble CD44 are significantly elevated in BCPs and associated with increases in HA and VEGF.  Increased sCD44 is related to bad patients' survival. As such, CD44 can be used as a prognostic marker in breast cancer patients.