Levosimendan, a new calcium sensitizer, was administered orally to 10 patients with severe congestive heart failure (CHF), who had a mean baseline pulmonary capillary wedge pressure (PCWP) of 22 mm Hg and a left ventricular ejection fraction of 23%. Each patient received 3 escalating doses of 1 mg, 2 mg, and 4 mg of levosimendan within 18–24 hours in an open-label pilot study. After administration of a 1-mg dose of levosimendan, PCWP decreased by 18% (p = 0.002) and cardiac output increased by 22% (p = 0.005). Diastolic blood pressure was decreased by about 5 mm Hg. Plasma catecholamine levels were unaffected. Plasma concentrations of levosimendan were unexpectedly low after administration of the 2-mg dose, and responses were weak. This was probably due to delayed drug absorption and altered baseline hemodynamics caused by ingestion of a meal before drug intake. The 4-mg dose of levosimendan was associated with a 27% increase in cardiac output (p = 0.009). PCWP showed only a small decrease, probably a result of relatively low baseline values (carryover from previous doses). Right atrial pressure decreased substantially by 40%. Heart rate increased by only 1–8 beats/min after administration of the 1- and 4-mg doses of levosimendan. It is concluded that oral levosimendan has favorable cardiac and hemodynamic effects in patients with severe CHF, and that these effects are similar to those seen after intravenous dosing with levosimendan in this patient group.