Background: Seroma is the most common complication occurs after mastectomy. It causes anxiety; pain; suture breakdown and may interfere with mobility of arm. The aim of this study was to assess the demographic, clinical and pathological parameters and their effect on seroma formation. Also assess different methods to reduce and prevent seroma formation. Patients and Methods: one hundred and twenty patients were randomized into three groups (40 in each group); Group I (Control Group); Group II (Compression-Dressing Group);Group III (quilting Group).The three groups were divided into subgroups (A and B) according to time of removal of the drain. All patients underwent Modified Radical Mastectomy and level II axillary dissection. Closed suction drains were placed. Results: Quilting technique significantly decrease the incidence of seroma (p=0.03); Total drain output in the first 7 days and the duration of drainage (p>0.001).Age; lymph nodes and pathological features of the tumor were not affecting seroma formation. Seroma was significantly lower in subgroup B (p= 0.011).Flap suturing, duration of drainage, body mass index(BMI), hypertension and diabetes mellitus were found to be significant Univariate predictors of seroma formation.Conclusion: Prevention is the golden key for management of seroma. Flap suturing, duration of drainage, BMI, hypertension and diabetes mellitus are the most important risk factors for seroma formation. Obliteration of dead space play a significant role in reduces postoperative seroma. Removal of suction drain after decrease the drain output to 20-30 ml has significant role in prevention of seroma formation