The pathogenesis of diabetic neuropathy is poorly understood. In this prospective study, we investigated the incidence rate and potential predictors for cardiovascular autonomic neuropathy (CAN) in a cohort of childhood-onset type 1 diabetic patients. Subjects from the Epidemiology of Diabetes Complications Study were examined at baseline and then biennially. CAN was diagnosed by abnormal (</=1. 1) expiration/inspiration ratio during deep breathing. During the 4. 7-year mean follow-up period, CAN developed in 104 patients from the 373 subjects who were free of CAN at baseline and provided follow-up data, an incidence-density of 5.9 cases/100 person-years. Cox proportional hazard modeling showed age (relative risk [RR]=2.15, p=0.0001), HbA1 (RR=1.50, p=0.0002) and nephropathy (albumin excretion >200 ug/min) (RR=2.46, p=0.0001) to be significant independent predictors. Hypertension was, however, predictive if nephropathy was not included in the model. We conclude that beyond age and poor glycemic control, nephropathy is a significant risk factor for CAN and this association may explain some of the increased mortality seen in CAN.