Background: Breast cancer is currently among the most common causes of mortality in women. Estrogen and its subsequent signaling pathways play an important role in the occurrence of breast cancer relapse. Tamoxifen is the most common breast cancer treatment option in ER+ patients, which acts as an adjuvant endocrinotherapy with X-ray and surgery. This approach is recommended as the first-line treatment and has increased the survival rate of breast cancer patients and reduced the relapse cases. However, we can observe resistance to tamoxifen and relapse cases in one-third of patients treated with this drug, which has become a major concern. Objective: The precise mechanisms of relapse and resistance to tamoxifen have not yet been identified and were explored in this study. Methods: Microarray profiles of relapse and relapse-free patients were investigated to explain the processes leading to relapse and possibly to tamoxifen resistance. Results: According to the preliminary analysis, 1460 genes showed increased expression while 1132 genes showed decreased expression. According to our default for inclusion (-2LogFC≥ + 2), 36 genes had increased expression (upregulated) while 33 genes had decreased expression (down-regulated). Conclusion: It seems that the mechanisms of resistance and relapse are multifactorial, and tumor cells induce relapse and resistance to tamoxifen through cell proliferation, survival, invasion, angiogenesis, extracellular matrix secretion, pump and membrane changes, and immune evasion.