Breast cancer is the most prevalent cancer type worldwide. In Egypt, It is the second most common type of cancer and the most common one in women with about 22 thousand new cases in 2020. Around 70% of newly diagnosed patients are hormone receptor-positive and, unfortunately, the disease is often diagnosed at the advanced stage. In postmenopausal women with hormone receptor-positive breast cancer, aromatase inhibitors (AIs) are the first-line adjuvant therapy according to National Comprehensive Cancer Network (NCCN) guidelines. Although, they showed superiority in efficacy to tamoxifen in this type of breast cancer, one of the most annoying adverse effects of the aromatase inhibitors are the vasomotor symptoms. They could be as severe as the patient would prefer discontinuing the medication. The underlying mechanism responsible for those adverse effects is that AIs suppress plasma estrogen levels by inhibiting the enzyme responsible for the conversion of androgens to estrogens in peripheral tissues. This estrogen depletion has been linked to an increase in hot flushes by decreasing endorphin levels and increasing that of norepinephrine and serotonin, followed by instability of the hypothalamic thermoregulatory set point which allows changes in the body temperature and in hot flash sensation. Hormone replacement therapy is considered first-line treatment for vasomotor symptoms. However, it is not preferred to be used in breast cancer patients especially those with hormone receptor positive breast cancer. So, many drugs have been investigated for their efficacy in reducing the frequency and severity of vasomotor symptoms. The only FDA-approved drug to treat moderate-to-severe vasomotor symptoms is paroxetine. Paroxetine is a selective serotonin reuptake inhibitor (SSRI) which is used mainly in major depressive disorder and other psychiatric conditions like anxiety disorders. It has proved an efficacy in reducing frequency and severity of hot flushes in post-menopausal women. But, there are several concerns regarding its use with tamoxifen in breast cancer patients. There is a competition between paroxetine and tamoxifen for hepatic CYP2D6, so, paroxetine prevents conversion of tamoxifen into its active metabolite. Oxybutynin has shown efficacy in relieving vasomotor symptoms. Oxybutynin is an anticholinergic used usually in urinary incontinence. It has an advantage over other SSRIs that it lacks the interaction with tamoxifen on CYP2D6 and, therefore, with the anticancer effect of tamoxifen treatment in breast cancer patients. To our knowledge, there are no head-to-head studies comparing the efficacy and safety of paroxetine versus oxybutynin in reducing frequency and severity of vasomotor symptoms especially in breast cancer patients taking aromatase inhibitors.