We performed a phase II study of oral vorinostat (200 mg twice daily, days 1-14 of a 21-day cycle), a histone and protein deacetylase inhibitor, to examine efficacy and tolerability in patients with relapsed/refractory Hodgkin lymphoma (HL) with ≤ 5 prior therapies. The primary endpoint was the objective response rate (ORR), with secondary endpoints of progression-free survival (PFS), overall survival (OS), safety and tolerability. A two-stage design was used for patient accrual. Twenty-five eligible patients were accrued in the first stage. Median time on treatment was 3.8 months. The ORR was 4% (one partial response). Median PFS was 4.8 months. The drug was well tolerated. The second stage of accrual was not opened due to few objective responses. Oral vorinostat has limited single-agent activity in relapsed/refractory HL. There was one partial response, while seven other patients had stable disease for > 1 year, including two with stable disease for nearly 3 years, suggesting that further studies in combination with other active agents in this setting may be warranted.