Background: Necrotizing soft tissue infections (NSTIs) are life-threatening infections characterized by progressive destruction of muscle, fascia, and overlying subcutaneous tissue. Prospective studies in the field are few, and data from the Indian subcontinent are bleak. Prompt diagnosis and timely treatment are critical for optimal outcomes. The aims of this study are to provide detailed information on the clinical profile of patients with NSTIs and to identify predictors of mortality in order to pick up reversible factors that may improve outcomes. Materials and methods: This study was a prospective cohort study of adult patients with NSTIs in a tertiary center in South India. All patients who were admitted to the surgical intensive care unit (ICU) of the institute with a diagnosis of NSTI were screened and enrolled. All patients were managed according to the local protocol for treatment of NSTIs and intensive care support. Results: In our cohort of patients, simple and multiple logistic regression analysis showed that four factors, namely, AKIN stage 3, shock, need for mechanical ventilation for more than 3 days, and low serum albumin values were found to be significantly associated with higher mortality. Conclusion: The successful management of these patients calls for early diagnosis, resuscitation, surgical debridement, appropriate and timely antibiotics, and early ventilatory weaning before multi-organ failure associated with shock and AKI occurs.