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Introduction The purpose of our study was to identify the key risk factors for the development of posterior reversible encephalopathy syndrome (PRES) after administration of the combination chemotherapy regimen, DA-EPOCH (dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin). Materials and Methods We performed a retrospective medical record review of patients receiving DA-EPOCH with or without rituximab (DA-EPOCH ± R) at our institution from July 2012 to September 2014. The patients were screened for evidence of severe neurotoxicity through identification of requests for neurology consultations or neuroimaging studies. Patients with evidence of central nervous system (CNS) neurotoxicity were reviewed in detail to identify documented cases of PRES. The key risk factors assessed included rituximab administration sequence, and the presence of CNS insults, fluid status or electrolyte abnormalities, organ dysfunction, and hypertension. Results A total of 44 patients received DA-EPOCH ± R at our institution from July 2012 to September 2014. Of these 44 patients, 3 (7%) were diagnosed with PRES. The patients who developed PRES were more likely to have a pre-existing CNS insult, fluid status or electrolytes abnormalities, and hypertension. Conclusion To the best of our knowledge, the present study is the first description of PRES associated with DA-EPOCH. The key risk factors for the development of PRES identified in our study included hypertension, fluid imbalance, electrolyte abnormalities, baseline organ dysfunction, a high tumor burden, and the presence of pre-existing CNS insults during chemotherapy, such as CNS infection. Patients with these risk factors appear to have a greater risk of developing PRES and should be monitored closely during treatment.