Background: Seroma is an abnormal collection of serous fluid in the dead space of post-mastectomy skin flaps and axilla or following breast-conserving surgery. Seroma is one of the most common early post-operative complications following surgery for breast cancer. Various studies report an incidence ranging from 10% to 85% following modified radical mastectomy (MRM) or axillary lymph node dissection (ALND). Objective: Evaluation of different modalities in the prevention of seroma formation post modified radical mastectomy. Patients and methods: This was a prospective comparative study carried out in the General Surgery Department, Faculty of Medicine, Aswan University, Aswan, Egypt. in the period between December 2017 and June 2018. Patients scheduled for modified radical mastectomy during the period of study were randomly divided into three groups, mastectomy flap fixation group (10 cases), ipsilateral shoulder immobilization group (10 cases) & (pre & post) operative tranexamic acid usage group (10 cases). Results: Hypertension, obesity, blood transfusion, and bloody field are at high risk of developing seroma after MRM; while DM, cancer stage, number of LN infiltrated and removed don't affect on seroma formation after MRM. Flap fixation was found to be the best modality in the prevention of seroma formation with a low incidence in developed seroma and other complications. On the other hand, tranexamic acid usage pre- and post-operative found that no role in the prevention of seroma formation after MRM. Conclusion: The mastectomy flap fixation technique is a valuable procedure that significantly decreases the incidence of seroma formation, and reduces the duration and amount of drained fluid.