Our goal was to perform a systematic review of the literature on the use of tromethamine (THAM) and its effects on intracranial pressure (ICP) in patients with neurological illness. All articles from MEDLINE, BIOSIS, EMBASE, Global Health, HealthStar, Scopus, Cochrane Library, the International Clinical Trials Registry Platform (inception to February 2014), reference lists of relevant articles, and gray literature were searched. Two reviewers independently identified all manuscripts pertaining to the administration of THAM in human patients that recorded effects on ICP. Secondary outcomes of effect on cerebral perfusion pressure, mean arterial pressure, patient outcome, and adverse effects were recorded. Two reviewers independently extracted data including population characteristics and treatment characteristics. The strength of evidence was adjudicated using both the Oxford and GRADE methodology. Our search strategy produced a total 2,268 citations. Twelve articles, 9 manuscripts, and 3 meeting proceedings were considered for the review with all utilizing THAM while documenting ICP in neurosurgical patients. All studies were prospective. Across all studies, there were a total of 488 patients studied, with 263 receiving THAM and 225 serving as controls in a variety of heterogeneous studies. All but one study documented a decrease in ICP with THAM administration, with both bolus and continuous infusions. One study documented a reduction in cerebral perfusion pressure. No significant renal dysfunction, hepatocellular injury, or hypoglycemia were reported. Three prospective randomized control trials displayed trends to improved outcome in severe traumatic brain injury (TBI) patients with THAM administration. There currently exists Oxford level 2b, GRADE B evidence to support that THAM reduces ICP in the TBI and malignant ischemic infarct population, with minimal side effects. The literature suggests THAM may be useful for ICP reduction in certain cases, though the safety of the compound in these circumstances is still unclear. Further prospective study is warranted.