There are little data regarding the use of massive transfusion protocols (MTP) outside of the trauma setting. This study compares the use of an MTP between trauma and non-trauma (NT) patients. Data were collected for trauma and NT patients from the prospectively maintained MTP database at a Level I trauma center over a 4-year period. Massive transfusion was defined as ≥ 10 units packed red blood cells (PRBCs) in a 24-hour period. Of 439 MTP activations, 37 (8%) were NT patients (64% male; mean age = 51 years, initial base deficit = -10.8). Activations were for gastrointestinal bleeding (n = 18), bleeding during surgery (n = 13), obstetrical complications (n = 5), and ruptured aortic aneurysm (n = 1). Over-activation of MTP (<10 units PRBCs/24 hours) was higher in NT than trauma patients (19/37, 51% vs 118/284, 29%, P < 0.01). For massive transfusion patients, 24-hour mortality was higher in NT compared with trauma patients (10/17, 59% vs 100/284, 35%, P = 0.05), but there was no difference in 30-day mortality (10/17, 59% vs 144/284, 51%, P = 0.51). With over-activation in 51% of NT patients, MTP usage outside of trauma is inefficient. Outcomes in NT patients were worse than trauma patients, which may be related to the underlying disease processes.