Plasma atrial natriuretic peptide (ANP) levels were examined in 66 patients with non-insulin-dependent diabetes mellitus (NIDDM), and in 9 age-matched normal controls and 18 hypertensive controls. The diabetic patients were classified into three groups according to random urine albumin/creatinine ratio (ACR, mg/g or mg/88.4 nM); group 1 (normo-albuminuria, ACR less than 20, n = 34), group 2 (borderline microcalbuminuria, 20 less than or equal to ACR less than 100, n = 17) and group 3 (manifest microalbuminuria and macroalbuminuria, 100 less than or equal to ACR less than 2000, n = 15). Plasma ANP levels (pg per ml) were significantly elevated in group 2 (46.0 +/- 19.0 SD) when compared with either normal controls (23.8 +/- 14.2), group 1 (28.9 +/- 15.6) or group 3 (26.0 +/- 12.9). This increase in plasma ANP levels was not related to hypertension. Furthermore, plasma ANP levels correlated positively with log(ACR) among the patients with ACR under 100 (groups 1 and 2 combined, r = 0.4701, p less than 0.01). These results suggest that an elevated plasma ANP level in the early phase of microalbuminuria possibly plays a pathophysiological role in the development of nephropathy in NIDDM patients.