We evaluated the comparative effects of furosemide, a short-acting loop diuretic, and azosemide, a long-acting loop diuretic, on neurohumoral factors and quality of life (QOL) in patients with congestive heart failure (CHF). Twenty-five stable patients with mild chronic CHF who had been administered furosemide (n = 14) or azosemide (n = 11) orally for more than 3 months were studied. We changed furosemide to azosemide or azosemide to furosemide and followed for 3 months. Echocardiography was performed, and we also measured neurohumoral factors and assessed QOL by questionnaire. Blood pressure, body weight, renal function and echocardiographic findings were the same during the furosemide and azosemide treatments. Plasma levels of atrial natriuretic peptide and brain natriuretic peptide were not different between the two treatments. However, plasma concentrations of active renin and norepinephrine were significantly higher with furosemide treatment than with azosemide treatment. QOL score was significantly lower with azosemide than with furosemide. These findings suggest that long-acting loop diuretics may have fewer adverse effects on the neuroendocrine system and QOL than short-acting loop diuretics in patients with mild CHF.