Background: Descending necrotizing mediastinitis (DNM) is a highly morbid infectious process. This uncommon disease process has carried historically a substantial burden of morbidity and mortality. In this study we hypothesized that application of a prospective modified management algorithm would decrease the morbidity and mortality from this highly destructive process. Methods: We developed a systematic approach for managing DNM, focusing on serial debridement guided by imaging, in conjunction with the use of broad-spectrum antibiotics and modern principles of critical care. We reviewed all patients admitted with this disease process from 2007-2012. Data collected included demographic information, co-morbidities, laboratory data including culture results, operative details, imaging frequency and findings, complications, and survival. Continuous variables were reported as median values and ranges. Results: From 2007-2010, we treated eight patients with DNM. The median age of the patients was 33 y (range 28-63 y), and 63% were male. In accordance with our algorithm, the patients underwent serial imaging at regular intervals following operative debridement. The median number of imaging studies was 11 (range 4-19). The patients required a median of five operative debridements (range 1-15). In five patients, drainage was necessary through a cervical exploration. A thoracic approach was required in six patients (two thoracoscopic, four via thoracotomy). Additional procedures included thymectomy (n=2), anterior mediastinotomy, carotid sheath exploration and resections of the clavicle, first rib, manubrium, pectoralis major muscle, and sternocleidomastoid muscle. The most common etiologic agents were Peptostreptococcus spp. and Streptococcus anginosus. Study patients received a median of six different antibiotics (range 2-10) for a total of 42 d (range 34-55 d). These patients were hospitalized for a median of 29 days (range 16-56 d), with 15 d (range 7-48 d) spent in the intensive care unit. Remarkably, the rate of survival was 100% (median follow-up of 33 mo). The patients developed no major complications, required no re-admissions, and had no re-infections. Conclusions: We applied an algorithmic approach to the treatment of DNM, consisting of aggressive operative debridement and enhanced by equally aggressive imaging. Our patients had excellent outcomes despite the widely known lethality of DNM. An aggressive approach may decrease complications and improve survival in this devastating disease process. Furthermore, our prospective experience with DNM suggests that this algorithm used in the present study should be the standard for managing patients with this challenging condition.