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Breast cancer is by far the most common cancer in women worldwide and the main cause of cancer-related mortality. Breast cancer accounts for 38% of all malignancies among Egyptian women. The aim of our study was to evaluate the serum levels of human epidermal growth factor receptor-2 (HER2), matrix metalloproteinase-9 (MMP-9), nitric oxide (NO), and total antioxidant capacity (TAC) in breast cancer patients and to correlate these markers with clinico-pathological parameters. Serum HER2, MMP-9, and carcinoma antigen 15-3 (CA 15-3) were assessed in 80 breast cancer patients and ten healthy subjects as a control group by the enzyme-linked immunosorbent assay (ELISA) technique while NO and TAC were assessed by a colorimetric method. Serum HER2 was≥ 15 ng/mL in nine patients (11.3%). High HER2 ECD levels were significantly associated with tissue HER2 (P< 0.0001), metastasis (P= 0.0024), and negativity of both estrogen (P= 0.0075) and progesterone (P= 0.0239) receptors. Serum MMP-9 (P= 0.0013), NO (P< 0.0001), and CA 15-3 (P< 0.0001) were significantly increased while serum TAC was significantly (P= 0.01) decreased in breast cancer patients as compared to the control group. Serum MMP-9 was increased significantly (P= 0.028) in metastatic patients as compared to non-metastatic patients. We found a positive correlation between serum HER2 and CA 15-3 (r= 36, p= 0.005). In conclusion, serum HER2 reflects the tissue HER2 status of breast cancer, so the determination of serum HER2 is helpful in assessing HER2 status, but in addition, a high level may reflect metastatic disease. Also, serum MMP-9 can be …