EPOCH is a preferred regimen for HIV-NHLs, which are frequently EBV+ or HHV-8+. The histone deacetylase (HDAC) inhibitor vorinostat disrupts EBV/HHV-8 latency, enhances chemotherapy-induced cell death, and may clear HIV reservoirs. To assess whether vorinostat increases EPOCH efficacy and/or HIV clearance we performed a randomized phase 2 study in 90 patients (45 per arm) with aggressive HIV-NHLs using dose-adjusted EPOCH (plus rituximab if CD20+) alone or with vorinostat 300 mg administered on days 1-5 of each cycle. Up to 1 prior cycle of systemic chemotherapy was allowed. The primary endpoint was complete response (CR). In 86 evaluable patients with diffuse large B-cell lymphoma (n=61), plasmablastic lymphoma (n=15), primary effusion lymphoma (n=7), unclassifiable B-cell NHL (n=2), and Burkitt lymphoma (n=1), CR rates were 74% versus 68% for EPOCH versus EPOCH-vorinostat, respectively (1-sided P=0.72). Patients with CD4+ count <200 cells/mm3 had a lower CR rate. EPOCH-vorinostat did not eliminate HIV reservoirs and resulted in more frequent grade 4 neutropenia and thrombocytopenia (47% and 29%, respectively) versus EPOCH (20% and 2%, respectively). The overall and event-free survival (EFS) rates were similar between arms. Overall, patients with Myc+ DLBCL had significantly lower EFS (44% at 3-yr, versus 83% in Myc- DLBCL). Low diagnosis-to-treatment interval (DTI) was also associated with inferior outcomes, while pre-protocol therapy had no negative impact. In conclusion, EPOCH had broad efficacy against highly aggressive HIV-NHLs, while vorinostat had no benefit; patients with Myc-driven DLBCL, low CD4, and low DTI had less favorable outcomes. Permitting pre-protocol therapy facilitated accruals without compromising outcomes. NCT0119384.