Seroma is the most common wound complication due to dead space remaining after mastectomy and axillary dissection. Seroma formation, which causes pain and tension, together with the limitations of shoulder and arm movements, can cause wound healing problems that can progress to wound dehiscence and flap necrosis. The aim of our study was to investigate the effects of continuous drainage and negative pressure wound therapy (NPWT) in breast cancer patients with refractory postmastectomy seroma. This retrospectively designed study was conducted with 27 patients who were referred to our center between 2018 and 2021 due to refractory seroma after mastectomy. The inclusion criteria of the study were the cases who were planned minimally invasive debridement and NPWT due to having refractory seroma formation with at least 200 cc and having interventions more than 1 month after modified radical mastectomy (MRM), despite conventional treatment methods. All patients' demographics, disease stage, history of possible neoadjuvant therapy, comorbidities, body mass index (BMI), number of wound dressings with NPWT, and total amount of NPWT accumulation were enrolled and compared statistically. Twenty-seven patients included in the study underwent continuous drainage after debridement, and 5 (3-9) dressings were treated with NPWT. None of the patients experienced complications after debridement and NPWT administration. In refractory seroma cases seen after postmastectomy, NPWT especially for the management of debridement and dead space can be evaluated as an appropriate treatment method in patients with high flow rate seroma.