Peripheral T-cell lymphomas (PTCL) are uniquely vulnerable to epigenetic modifiers. We demonstrated in vitro synergism between histone deacetylase inhibitors and DNA methyltransferase inhibitors in preclinical models of T-cell lymphoma. In a phase 1 trial we found oral 5-azacytidine (AZA) and romidepsin (ROMI) to be safe and effective, with lineage-selective activity among patients with relapsed/refractory (R/R) PTCL. Patients with treatment-naïve (TN) or R/R PTCL received AZA 300 mg daily, days 1-14 and ROMI 14 mg/m2, days 8, 15, and 22, every 35 days. The primary objective was overall response rate (ORR). Targeted next-generation sequencing was performed on tumor samples to correlate mutational profiles and response. Among 25 enrolled patients the ORR and complete response rates were 61% and 48%, respectively. However, patients with T-follicular helper cell (tTFH) phenotype exhibited higher ORR (80%) and complete remission rate (67%). The most frequent grade 3-4 adverse events were thrombocytopenia (48%), neutropenia (40%), lymphopenia (32%) and anemia (16%). At a median follow-up of 13.5 months the median PFS, DOR, and OS were 8.0 months, 20.3 months, and not reached, respectively. The median PFS and OS were 8.0 months and 20.6 months, respectively, in patients with R/R disease. Patients with tTFH enjoyed a particularly long median survival (median not reached). Responders harbored a higher average number of mutations in genes involved in DNA methylation and histone deacetylation. Combined AZA and ROMI are highly active in PTCL patients and could serve as a platform for novel regimens in this disease. The trial was registered at www.clinicaltrials.gov, #NCT01998035.Copyright © 2020 American Society of Hematology.