Purpose: Romidepsin is a potent histone deacetylase inhibitor under clinical development. The objective of this study was to evaluate the effect of demographic, clinical, and pharmacogenetic covariates on the pharmacokinetics of romidepsin in patients withT-cell lymphoma. Experimental Design: Pharmacokinetic assessment was done in 98 patients enrolled in a phase II study who received 14 or 18 mg/m 2 of romidepsin as a 4-hour infusion on day 1 during their first treatment cycle. Population modeling was done using a nonlinear mixed effects modeling approach to explore the effects of polymorphic variations in CYP3A4, CYP3A5, SLC01B3, and ABCB1, all of which encode genes thought to be involved in romidepsin disposition. Results: A two-compartment model with linear kinetics adequately described the romidepsin disposition. Population clearance was 15.9 L/h with between-patient variability of 37%. ABCB1 2677G>T/A variant alleles tended toward a reduced clearance and lower volume of tissue distribution, but this was not supported by a statistical significance. Genetic variations in CYP3A4/5 and SCLO1B3 had no effect on the systemic exposure. Conclusion: The population pharmacokinetic analysis indicates moderate interindividual variability in romidepsin pharmacokinetics and no clinically relevant covariates associated with the unexplained pharmacokinetic variability of romidepsin in this population.