To determine the reliability and validity of a patient outcome questionnaire for chronic heart failure, a randomized, double-blind, placebo-controlled, 3-month trial of pimobendan, an investigational medication with inotropic and vasodilator activities, was performed. Evaluated were 198 ambulatory patients with primarily New York Heart Association (NYHA) class III heart failure from 20 referral centers. Baseline therapy included digoxin, diuretics and, in 80%, a converting enzyme inhibitor. Oral pimobendan at 2.5 (n = 49), 5.0 (n = 51), or 10 (n = 49) mg daily or matching placebo (n = 49) was administered. The Minnesota Living with Heart Failure (LIhFE) questionnaire was a primary outcome measure, along with an exercise test. Interitem correlations identified subgroups of questions representing physical and emotional dimensions. Repeated baseline scores were highly correlated (r = 0.93), as were the physical (r = 0.89) and emotional (r = 0.88) dimension scores. Placebo did not have a significant effect with median (25th, 75th percentile) changes from baseline scores of 1 (-3, 5), 1 (-2, 3), and 0 (-1, 2), respectively (all p values > 0.10). The 5 mg dose significantly improved the total score, 7.5 (0, 18; p = 0.01) and the physical dimension, 4 (0, 8; p = 0.01), compared with placebo. Changes in the total (r = 0.33; p < 0.01) and physical (r = 0.35; p < 0.01) scores were weakly related to changes in exercise times, but corresponded well with changes in patients' ratings of dyspnea and fatigue. These data suggest that the LIhFE questionnaire was a reliable and valid patient self-assessment of the therapeutic benefit from pimobendan.