FTY720 is a sphingosine‐1‐phosphate receptor agonist being developed as an immunomodulator for acute rejection prophylaxis after organ transplantation. This study was performed to characterize the pharmacokinetics of and lymphocyte response to multiple‐dose FTY720. In this randomized, double‐blind study, three groups of 20 healthy subjects each received either placebo, 1.25 mg/day FTY720, or 5 mg/day FTY720 for 7 consecutive days. FTY720 blood concentrations and lymphocyte counts were assessed over the weeklong treatment phase and over a month‐long washout phase. The relationship between FTY720 blood concentrations and lymphocyte counts was explored by an inhibitory E_max model. First‐dose exposure was consistent with dose proportionality between the low‐ and high‐dose groups. Blood levels accumulated fivefold over the treatment period. Exposure on day 7 was dose proportional for C_max (5.0 ± 1.0 vs. 18.2 ± 4.1 ng/mL) and for AUC (109 ± 24 vs. 399 ±85 ng•h/ mL). Washout pharmacokinetics after the last dose indicated an elimination half‐life averaging 8 days. Lymphocyte counts decreased by 80% in subjects receiving the lower dose to a nadir of 0.4 ± 0.1 × 10⁹/L and by 88% in subjects receiving the upper dose to a nadir of 0.2 ±0.1 ×10⁹/L. Descriptive exposure‐response modeling estimated that the lymphocyte response at 5 mg/day is near the maximal response achievable. By the end‐of‐study evaluation on day 35, lymphocyte counts had recovered to within 75% and 50% of baseline in the low‐ and high‐dose groups, respectively. In summary, systemic exposure to FTY720 was consistent with dose‐proportionality after both single‐ and multiple‐dose administration. Total lymphocyte counts decreased from baseline by 80% and 88% at regimens of 1.25 and 5 mg/day, respectively. Exposure‐response modeling provided evidence that 5 mg/day FTY720 resulted in a near‐maximal dynamic effect of this drug on lymphocytes.