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Novel coronavirus-19 (COVID-19) variants continue to spread worldwide with the development of highly transmissible strains. Several guidelines addressing management of cancer patients during the COVID-19 pandemic have been published, primarily based upon expert opinion. The COVID-19 pandemic has affected all aspects of breast cancer care including screening, diagnosis, treatment, and long-term follow-up. Recent reports indicate that mRNA COVID-19 vaccines can provoke lymphadenopathy in both cancer patients and healthy individuals. Unilateral axillary lymphadenopathy (UAL) post-COVID-19 vaccination is a challenging presentation for cancer patients because of the potential for misinterpretation as malignancy. The World Health Organization’s target to vaccinate 70% of the world’s population by mid-2023 is likely to increase the incidence of post-COVID-19 vaccination UAL. In this article, we review the published evidence regarding UAL post-COVID-19 vaccination and present diverse cases of breast cancer patients where false-positive UAL post-COVID-19 vaccination proved to be a therapeutic challenge. The United Arab Emirates (UAE) vaccination program is well ahead of other countries in the world, having accomplished the target of 100% vaccination of the population with at least one dose. Therefore, an increasing number of recently vaccinated patients are likely to present with UAL, detected by surveillance imaging, post-vaccination. We have therefore made recommendations regarding the management of cancer patients with UAL post-COVID-19 vaccination in order to avoid misdiagnosis and unnecessary imaging or invasive biopsy procedures.