In order to study the influence of gender on circulating levels of cardiac natriuretic hormones (CNHs) in heart failure, we measured the plasma levels of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) by means of highly sensitive and specific IRMA methods in 239 consecutive patients (age 64.7 +/- 11.6 years, range 21-89 years; 170 men and 69 women) with cardiomyopathy. There was different response of CNH according to gender in patients with heart failure, as indicated by the ratio between the individual CNH values of patients and the gender-specific cut-off values. Indeed, the mean ratio for ANP found in men (3.6 +/- 3.6) was significantly higher (p = 0.0075) than that found in women (2.4 +/- 2.1). The mean ratio for BNP was on average 2.3 fold higher (15.9 +/- 27.1 in men and 6.9 +/- 6.8 in women, p = 0.0084). Moreover, age, ejection fraction, and disease severity independently and significantly contributed to regression with both ANP (R = 0.612, F = 39.969, p < 0.0001) and BNP (R = 0.656, F = 49.957, p < 0.0001) values, while gender did not. In conclusion, our study suggests a different, gender-specific activation of the CNH system in this clinical condition, although age, ejection fraction and disease severity seem to be more powerful predictors than gender of circulating levels of ANP and BNP in patients with heart failure.