Following advances in critical care, in-hospital multiple organ failure–related mortality is declining. Consequently, incidence of chronic critical illness is increasing. These patients linger in the intensive care unit, have high resource utilization, and poor long-term outcomes. Within this population, the authors propose that a substantial subset of patients have a new phenotype: persistent inflammation, immunosuppression, and catabolism syndrome. There is evidence that myelodysplasia with expansion of myeloid-derived suppressor cells, innate and adaptive immune suppression, and protein catabolism with malnutrition are major contributors. Optimal care of these patients will require novel multimodality interventions.