One of the leading causes of morbidity and early-age mortality across the globe is trauma. It disrupts immune system homeostasis and intensely affects the innate and adaptive immune responses, predisposing patients to posttrauma complications and poor outcomes. Most of the studies on posttrauma cellular immune response have been centered on the T helper-1-T helper-2 imbalances after trauma. This study was conducted to understand the role of circulating novel T helper cells in the acute posttraumatic period and clinical outcome of trauma patients. Signature cytokines and transcription factors of circulating Th (T helper)-9, Th-17, Th-22, and regulatory T helper cells were studied using flowcytometry along with serum biomarkers in 49 patients with polytraumatic injuries admitted to a tertiary care hospital. The patients were followed up until their outcome. The results were correlated with their clinical outcomes. In patients who died, higher nTreg, iTreg, Tr1 (early-phase), and higher IRF4+Th-9, IL17+ Th-17, and RORγT+ Th-17 (mid-phase) were seen. However, by the late phase, only RORγT+ Th-17 remained higher. Serum IL-6 and PCT were found to be consistently higher. In survivors, higher Th-3 (early phase), Th-22 (mid-phase), and IRF4+Th-9, IL17+ Th-17, nTreg, Th-3 (late phase) were observed to have played a protective role. Serum IL-2, IL-4, IL-17A and IL-22 were significantly higher in survivors. Different T helper subsets were observed to be playing pathogenic and protective roles in different phases of trauma and could be used for early prognostication and make way for noninvasive management of critically injured trauma patients by immunomodulation. Khurana S, Bhardwaj N, Kumar S, Sagar S, Pal R, Soni KD, et al. Crosstalk between T Helper Cell Subsets and Their Roles in Immunopathogenesis and Outcome of Polytrauma Patients. Indian J Crit Care Med 2020;24(11):1037-1044.