Patients with non-insulin-dependent diabetes mellitus (NIDDM) and microalbuminuria (MA) are at increased risk of early death. In NIDDM patients without evidence of heart disease, we examined the links between MA and autonomic neuropathy (AN) and reduced heart rate variability (HRV), both of which have been linked to a poor prognosis. We have studied 43 asymptomatic NIDDM patients with MA and have matched them with 43 normoalbuminuric patients for age, gender, diabetes duration, and smoking status. AN was assessed by heart rate changes to deep breathing, Valsalva, and posture and blood pressure changes to posture and hand grip. Twenty-four hour Holter monitoring was used to evaluate HRV. Patients with MA showed evidence of AN and reduced HRV when compared with normoalbuminuric patients. In multivariate analysis, with measures of AN and HRV as outcome variables, Log albumin excretion rate was a significant independent predictor but stronger predictors were the presence of diabetic retinopathy, age, body mass index, claudication, alcohol consumption, and calcium channel blocker use. The presence of MA is linked to AN and reduced HRV in asymptomatic NIDDM patients. The nature of the relationship is complex, involving multiple relationships with other clinical parameters.