Romidepsin is the second histone deacetylase inhibitor (HDACi) approved for the treatment of advanced stages of cutaneous T‐cell lymphoma (CTCL). Recent in vitro data suggest that HDACis suppress immune function although these findings have not been confirmed in patients. Thus, we serially examined the cellular immune function of eight CTCL patients undergoing treatment with three cycles of romidepsin. We measured the patients' natural killer (NK) and dendritic cell (DC) function and performed an in vitro terminal deoxynucleotidyl transferase dUTP nick end labeling assay to measure cellular apoptosis. Patients' NK cell cytolytic activity decreased from baseline to the third cycle of treatment (P = 0.018) but stimulation with a toll‐like receptor (TLR) agonist increased this activity (P = 0.018). At baseline, a TLR agonist could both activate patients' DC (P = 0.043) and stimulate interleukin‐12 protein production (P = 0.043) but both were suppressed after the first cycle of romidepsin. Finally, we observed increased specificity for romidepsin‐induced CD4+ tumor cell apoptosis and dose‐dependent increases in cellular apoptosis of healthy cells in multiple lineages (P < 0.05). These findings raise concern that HDACis suppress immune function in CTCL patients and they support the concurrent use of multiple immune stimulatory agents to preserve the host immune response. Am. J. Hematol. 2012. © 2012 Wiley Periodicals, Inc.