Background Seroma formation, the most prevalent postoperative complication after mastectomy, is an inflammatory process that is potentially preventable via local steroid administration. This study investigated the effect of local steroid administration on seroma formation. Methods This was a double-blind randomized placebo-controlled intervention study of a single dose of 80-mg methylprednisolone versus saline on seroma formation after mastectomy. Patients were further classified according to the surgical axillary procedure: mastectomy with sentinel lymph node biopsy (M-+-SLNB) or mastectomy with level I-II axillary lymph node dissection (M-+-ALND). Treatments were administered into the wound cavity via the drain orifice following removal of the drain on the first day after surgery. The primary endpoint was seroma formation; secondary endpoints included the frequency of side-effects and complications. Results A total of 212 women scheduled for mastectomy for primary breast cancer were included. After M-+-SLNB, 32 (46 per cent) of 69 women developed a seroma in the methylprednisolone group, compared with 52 (78 per cent) of 67 in the saline group (P-<-0·001). The mean cumulative seroma volume in the intention-to-treat population for the first 10 and 30-days was significantly lower in the methylprednisolone group (24-ml versus 127-ml in the saline group, and 177 versus 328-ml respectively) (P-<-0·001). After M-+-ALND, similar proportions of patients developed a seroma in the methylprednisolone (35 of 37, 95 per cent) and saline (34 of 36, 94 per cent) groups, and methylprednisolone administration had no significant effect on seroma formation. No differences in infection rate were observed. Conclusion Methylprednisolone administered into the wound cavity on the first day after M-+-SLNB exerted a highly significant preventive effect against seroma formation during the next 30-days. This effect was not seen in the M-+-ALND group. Future studies may clarify whether higher or repeated methylprednisolone doses increase the efficacy. Simple way to prevent seroma.