<p>Trastuzumab is a common and effective therapeutic choice for breast cancer treatment. However, the cardiotoxicity induced by this therapy remains a significant challenge, because we lack predictors that help avoid allocating some patients with high risk to this management plan. This study was aimed to evaluate several baseline risk factors such as prolonged QTc interval, age, and lower expression level of estrogen and progesterone receptors that might predict cardiac toxicity after Trastuzumab therapy. This prospective observational study was conducted in Al-Bairouni Hospital at Damascus University. Patients were evaluated with echocardiography and electrocardiography before therapy and three weeks after the last administration of the fourth cycle. A significant Trastuzumab-related cardiotoxicity was determined by a 5% or more reduction in the left ventricular ejection fraction after excluding all other potential causes. A total number of 140 patients with breast cancer, who were indicated Trastuzumab therapy, were recruited for this study. Thirty of them (21.4%) developed Trastuzumab-related cardiotoxicity but all were asymptomatic. Corrected QT interval of more than 450 ms and lower expression level of estrogen and progesterone receptors at baseline were associated with higher susceptibility to develop Trastuzumab-related cardiotoxicity (<i>P</i> = 0.045, <i>P</i> = 0.004, and <i>P</i> = 0.042, respectively). Of note, preexisting cardiac morbidities, age, and chemotherapy accompanying Trastuzumab administration did not reach significant association with cardiotoxicity. Breast cancer patients with prolonged corrected QT interval or lower expression levels of hormone receptors are at a higher risk of developing Trastuzumab-related cardiotoxicity, necessitating careful administration of the therapy.</p>