Objectives: Intrathoracic pressure regulation therapy (IPRT) has been shown to increase blood pressure in hypotensive patients. The potential value of this therapy in patients with hypotension secondary to trauma with bleeding is not well understood. Hypothesis: We hypothesized that IPRT would non-invasively and safely enhance blood pressure in spontaneously breathing patients with trauma-induced hypotension. Methods: This prospective observational cohort study assessed vital signs from hypotensive patients with a systolic blood pressure (SBP) ≤90 mmHg secondary to trauma treated by pre-hospital emergency medical personnel with IPRT (ResQGARD) in three large US metropolitan areas. Upon determination of hypotension, facemask-based IPRT was initiated as long as bleeding was controlled. Vital signs were recorded before, during, and after IPRT. An increased SBP with IPRT use was the primary study endpoint. Device tolerance and ease of use were also reported. Results: A total of 54 patients with hypotension secondary to trauma were treated from 2009 to 2016. The mean (± SD) SBP increased from 81 ± 12 mmHg to 107 ± 19 with IPRT (p < 0.0001) and mean arterial pressures (MAP) increased from 62 ± 11 mmHg to 82 ± 17 (p < 0.0001). There were no significant changes in mean heart rate or oxygen saturation. Approximately 75% of patients reported moderate to easy tolerance of the device. There were no safety concerns or reported adverse events. Conclusion: In patients with hypotension secondary to trauma IPRT increased blood pressure to levels known to provide near normal or normal vital organ blood flow in the vast majority of patients. Patients were treated safely and not over resuscitated with this intervention. These findings support the use of IPRT to treat trauma-induced hypotension as long as bleeding has been controlled.