Introduction The incidence of Ifosfamide-induced encephalopathy (IIE) ranges from 5-30%. Aprepitant and fosaprepitant may increase the risk of IIE; however, data is limited. The objective of this study was to characterize the incidence of IIE in patients receiving concomitant fosaprepitant. Methods This single-center, retrospective chart review included adult patients diagnosed with sarcoma who received at least one administration of high dose ifosfamide (≥1800mg/m2) and fosaprepitant between January 2017 and June 2018. The primary endpoint was the percentage of patient cycles in which IIE was experienced. Secondary endpoints included characterization of IIE management strategies, time to IIE resolution, and the incidence of IIE upon ifosfamide re-challenge. Subgroup analyses were performed to assess whether the following variables predisposed a patient to neurotoxicity: elevated serum creatinine, hypoalbuminemia, metabolic acidosis, hyperbilirubinemia, shorter infusion time, and higher body mass index. The role of CYP2B6 inhibitors and prior cisplatin use were also examined. Results Fifty-one patients who received 215 total cycles of ifosfamide were included. Twenty (9.3%) patient cycles included documented evidence of IIE. The most common management strategies were to prolong the infusion time and administer methylene blue. The mean time to resolution of IIE was 2.58 days. The incidence of secondary IIE upon re-challenge was 26.3%. Baseline albumin <3.5 g/dL (p<0.001) was statistically associated with the development of IIE. Conclusion Co-administration of fosaprepitant and ifosfamide in sarcoma appears to be safe. Hypoalbuminemia was a notable risk factor confirmed in this study. Further research is needed to delineate IIE risk factors.