We performed a study to assess cardiac output (CO) and total peripheral resistance (TPR) at rest and during peak exercise with the goal to better define the role of these parameters in the development of hypertension in children with chronic kidney disease (CKD) stage 2-4. Fifty-two pediatric patients with CKD (mean age 12.7+/-3.7 years) and 28 healthy individuals of comparable age and sex participated in the study. At rest, children with CKD had a significantly higher systolic and diastolic blood pressure (BP) and calculated mean arterial pressure (MAP) than healthy controls. Total peripheral resistance was significantly higher in children with CKD than in controls (1627.7+/-534.6 vs 1354.6+/-338.9 dynexsxcm(-5), p =0.02). There was no significant difference in heart rate or CO between the two groups. Children taking antihypertensive medications had lower TPR than children without BP medications (1514.6+/-439.6 vs 1788.2+/-505.4 dynexsxcm(-5), respectively, p =0.06). At peak exercise, children with CKD had a significant increase in MAP, heart rate and CO and had a significant decrease in TPR (difference between rest and peak exercise: -782.4+/-375.9 dynexsxcm(-5), p <0.001). Children taking BP medications had blunted MAP and CO responses when compared to controls (Delta CO: 6.2+/-2.8 l/min vs 9.8+/-4.5 l/min, respectively, p =0.01; MAP: 13.9+/-10.2 mmHg vs 21.5+/-11.7 mmHg, respectively, p =0.01). Children without BP medications had a similar to controls response to exercise in respect to CO, MAP and TPR. We conclude that increased TPR is a major contributor to elevated blood pressure in children with CKD and suggest that BP medications decreasing vascular resistance should be used as a first line of antihypertensive therapy in these patients.