Abstract Background: Mastectomies with immediate implant-based reconstruction are increasingly common, particularly among younger breast cancer (BC) patients and individuals undergoing risk-reducing surgery. Skin-sparing and nipple-sparing mastectomies are now well-established techniques; however, they are associated with specific postoperative complications. Notably, prolonged drain duration and seroma formation can hinder recovery, increasing the risk of infection, potentially requiring further intervention. Identifying risk factors for seroma formation is crucial to improving postoperative outcomes and guiding surgical planning. Methods: All nipple-sparing and skin-sparing mastectomies performed at a high-volume German breast center between January 2017 and June 2024 were retrospectively analyzed. A total of 1,298 mastectomies in 756 patients were included. Patient demographics, clinical characteristics, and perioperative data were evaluated. Seroma formation was defined as either a drain remaining in place beyond postoperative day 7 or the need for seroma aspiration following drain removal. Results: Among the 1,298 mastectomies, 389 (30.0%) met the criteria for seroma formation. Oncologic indications (e.g., DCIS or invasive BC) were significantly associated with higher rates of seroma formation compared to risk-reducing procedures. Older age, higher BMI, and the presence of medically treated hypertension were also significantly associated with increased seroma risk. No significant associations were found with neoadjuvant chemotherapy, diabetes, smoking status, or anticoagulant use. The type of mastectomy (skin-sparing vs. nipple-sparing), the use of mesh for stabilization, and the plane of reconstruction (prepectoral vs. retropectoral) did not affect the incidence of seroma. However, higher implant weight and greater drain output within the first three postoperative days were strongly correlated with seroma formation (p 0.001). Patients in the seroma group experienced significantly more postoperative infections (8.0% vs. 2.6%, p 0.001), although rates of revision surgery and delayed wound healing were not significantly different. Conclusion: This large retrospective cohort study identifies key clinical and surgical factors associated with seroma formation following mastectomy with immediate reconstruction. These findings underscore the importance of individualized risk assessment and may inform patient counseling and surgical decision-making to reduce postoperative morbidity. Citation Format: K. Pfister, H. Schäffler, E. Leinert, K. Veselinovic, J. Haager, S. Lukac, S. Huesmann, B. Rack, W. Janni, V. Fink. Foreseeing Fluid: Risk Factors for Seroma Formation Following Skin- and Nipple-Sparing Mastectomy with Immediate Reconstruction abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS2-03-19.
Pfister et al. (Tue,) studied this question.