Seroma is a frequent complication after breast cancer surgery. Closed suction drainage for several days is the standard procedure to reduce seroma formation. The aim of this study was to compare the efficacy of external compression dressing, suture flap fixation, and the conventional method of closed suction drains in the prevention of seroma formation. A total of 161 patients were prospectively randomized in a three groups × two subgroups design into control (n= 48), compression dressing (n= 53) and suturing groups (n= 49), and two subgroups, conventional drain removal (n= 75) and early drain removal (n= 75). All patients underwent ALND as part of MRM or BCT. The primary end point was the incidence of seroma. Suture flap fixation significantly reduced the incidence of seroma (p = 0.003), total drain output (p = 0.005), and duration of drainage (p = 0.001) without increase in wound complications. Compression dressing reduced duration of drainage significantly (p = 0.03), but not the total drain output (p = 0.15) or seromas (p = 0.58). Early drain removal on postoperative day 7 irrespective of drain output does not significantly increase seroma formation (p = 0.34) or wound complications. On multivariate analysis, BMI ≥ 30 (p = 0.02) and longer duration of drainage (p = 0.04) were identified as independent predictors for seroma formation. Obliteration of the dead space after breast cancer surgery by suture flap fixation is a safe and easy procedure, which significantly reduces postoperative seroma formation and duration of drainage. Compression dressing offers no advantage over normal dressing. Drains can be removed safely on postoperative day 7 irrespective of output without significant increase in complications.