Background: Plasmablastic lymphoma (PBL) is a rare and aggressive subtype of B-cell lymphoma with a predominant occurrence in patients with HIV and other immune compromised states. It commonly affects the jaw and oral cavity but has also been described involving the gastrointestinal tract, bone, bone marrow, and lymph nodes. The historical treatment regimens have typically included CHOP, but more recently dose-adjusted EPOCH has become the standard for HIV-associated lymphomas. It is unclear if regimens other than CHOP can significantly improve the outcome in patients with PBL. Methods: We identified 25 patients with PBL at Parkland Hospital treated between 2000 to 2012. Data regarding patient age, gender, HIV status, initiation of antiretroviral therapy, immunophenotype, EBV status, administration of radiotherapy and primary site of presentation were recorded. Log-rank test was used to assess differences in survival by treatment regimen. Results: The median age at presentation was 44 years with a 4:1 male predominance. Most (92%) were infected with HIV and had a median CD4+ count of 87 cells/mm3. A minority of patients (32%) were on antiretroviral therapy at the time of diagnosis. The most common primary sites of disease were oral/maxillofacial sites and the gastrointestinal tract with most patients presenting with stage III or IV disease (64%). EBV was detected in the majority of cases (91%) and HHV-8 was detected in none of the cases. CD20 positivity was rare (12%). MYC rearrangements were described in 32% of the cases. Chemotherapy was used to treat most patients (76%) with EPOCH being the most common treatment choice (56%). Radiotherapy was administered in 28% of patients. Primary refractory disease was observed in 16% of the patients. The median overall survival observed in all patients who received chemotherapy was 11.6 months (range 2-63 months). Those who were treated with EPOCH demonstrated a better median overall survival (17 months) compared to those treated with CHOP and CHOP-like regimens (7 months, p=0.04). Conclusions: This retrospective single center study suggests that EPOCH may improve survival in PBL.