Seroma is a common problem after mastectomy, occurring in 30-92% of cases. The aim of this study was to detect the histopathology of postmastectomy seromas and the related changes in tumor necrosis factor-α (TNF-α) serum levels. Unilateral mastectomies were performed on 45 female albino rabbits. On day 7, the area of mastectomy was palpated for the presence of swelling and any fluid was aspirated. A biochemical assay of TNF-α serum from all animals (with and without seroma) and that found in the aspirated fluid was performed. Skin flaps and underlying tissues of the mastectomy region were dissected, fixed in 10% formalin, processed and stained for histopathological examination. Seroma developed in 46.6% of the rabbits. The mean volume of seroma fluids was 3.03±2.21 mL. The level of TNF-α in the serum of rabbits that developed seroma was significantly higher than in those that did not. The tissue surrounding the seromas showed persistent granulation tissue containing fibroblasts, inflammatory cells and a large number of newly formed blood vessels surrounded by extravasated blood. This could be attributed to the increased TNF-α serum level, as discovered by the biochemical study. The inflammatory cell infiltrates mainly consisted of eosinophils as well as lymphocytes, macrophages and plasma cells. The postmastectomy seromas showed altered and delayed wound healing. TNF-α levels were elevated in both the seroma fluid and the serum of animals that developed seroma, possibly indicating its role in seroma development.