Cyclic GMP (cGMP) serves as an intracellular second messenger of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and nitric oxide (NO) and its peripheral blood concentration is an index of its biological activity. It has been reported that the plasma concentration of cGMP is correlated with the concentrations of ANP and BNP and is related to the prognosis of chronic heart failure patients, but the relation with NO has not been studied. Therefore, we investigated the roles of ANP, BNP, and NO in relation to cGMP in the blood during worsening and improvement of chronic heart failure. The subjects were 25 patients who were hospitalized in our hospital for acute worsening of chronic heart failure. Plasma concentrations of NO, norepinephrine (NE), ANP, BNP, and cGMP were measured on acute worsening (admission) and improvement (discharge) of heart failure. The cGMP concentration on worsening showed a positive correlation with the NO concentration (r = 0.57, P < 0.01), but no correlations with ANP or BNP were observed. The cGMP concentration on improvement showed no correlation with the NO concentration, but a positive correlation with ANP (r = 0.69, P < 0.001) and BNP (r = 0.67, P < 0.001). No correlation was observed between the NO and NE concentrations. We also studied serious cases of NYHA IV and mild cases of NYHA II to III. The cGMP concentration in the serious group showed a positive correlation with the NO concentration but no correlations with ANP or BNP concentrations on worsening. However, in the mild group, the cGMP concentration during worsening showed positive correlations with both the NO and BNP concentrations. On improvement, the cGMP concentration showed no correlation with the NO concentration but positive correlations with both the ANP and BNP concentrations in both the severe and mild groups. The results suggest the possibility that cGMP is produced mainly by NO during worsening, and by ANP and BNP rather than NO during improvement of chronic heart failure.