Background. This multicenter trial was conducted to determine the efficacy and safety of pimobendan, an inotropic agent with calcium-sensitizing properties and activity as a phosphodiesterase inhibitor, in patients with heart failure. Methods and Results. One hundred ninety-eight ambulatory patients with symptoms of moderate to severe heart failure despite therapy with digitalis and diuretics with or without a single vasodilator were randomly assigned to receive either placebo (n=49) or pimobendan (n=149) in a double-blind fashion for 12 weeks. A dose range of pimobendan was used including 2.5 (n=49), 5 (n=51), or 10 mg/day (n=49). One hundred fifty-eight (80%) patients were taking a converting enzyme inhibitor (CEI) and 28 (14%) patients were taking a non-CEI vasodilator. At end point, the 5-mg dose of pimobendan significantly increased exercise duration compared with placebo (121.6±19.1 seconds, p<0.001), whereas the 10-mg dose produced an increase of borderline significance (81.1±19.5 seconds, p=0.05). Peak V̇O2 was significantly increased by 2.23±0.58 ml/kg/min in the 5-mg group (p<0.01 versus placebo). Furthermore, quality of life measured with the Minnesota Living With Heart Failure Questionnaire improved by 8.5±2.3 units in the 5- mg group compared with 1.3±2.2 units in the placebo group (p<0.01). There were a total of 23 all-cause hospitalizations in the placebo group, which was significantly greater compared with 33 in the three groups treated with pimobendan (p<0.01). There were no significant differences between the placebo and pimobendan groups with respect to changes in ejection fraction and plasma norepinephrine measured at baseline and at the completion of the 12-week study, proarrhythmic effect, or the number of patients with a significant adjustment in background therapy. Eleven patients died, including three (6%) on placebo and eight (5%) on pimobendan (p=NS). Among all adverse events, headache tended to be more common in the pimobendan groups compared with placebo, with the incidence increasing with dose (p<0.05). Conclusions. These data demonstrate that pimobendan significantly increases exercise duration, peak V̇O2, and quality of life in patients with heart failure. Pimobendan appears to be useful adjunctive therapy when added to digitalis, diuretics, and vasodilators.