Objective:To evaluate accuracy and repeatability of blood volume determinations made by the carbon monoxide method, using a ventilator-driven administration system.Design:Prospective within-patient comparison, using simultaneous measurements by two methods to determine accuracy. Prospective laboratory investigation in animals to estimate repeatability.Subjects:For accuracy: Nineteen ventilated critically ill patients in a university hospital intensive care unit. For repeatability: Six anesthetized, mechanically ventilated normovolemic pigs because this is impossible to perform in humans.Interventions:In the accuracy study, a small mass of carbon monoxide was administered via a closed breathing system and arterial blood samples were taken from existing cannulas. In the repeatability study, an intramuscular sedative was given, followed by an inhalational anesthetic induction and mechanical ventilation via a tracheal tube. Left axillary artery and external jugular vein cannulas were sited. Anesthesia was maintained using an intravenous infusion. Five sequential circulating hemoglobin and blood volume estimations were made using the carbon monoxide method.Measurements and Main Results:The small carboxyhemoglobin increase produced by uptake of a small, known mass of carbon monoxide was used to estimate the circulating blood volume. Simultaneous measurement, using51Cr-labeled red blood cells, was performed.Twenty measurements were made in 19 patients. The bias (mean difference between blood volume measurements by the two methods) was 397 mL (5.53 mL·kg−1) ±415 mL (±5.95 mL·kg−1); the limits of agreement (mean difference ±2 SD) were −433 mL and 1227 mL (−6.36 mL·kg−1and 17.42 mL·kg−1). Therefore, 95% of expected differences will lie between these limits. The mean blood volume was 75.8 mL·kg−1in the animals. The coefficient of variation of repeated estimates was 9.49%. Mean circulating hemoglobin mass was 7.31 mmol with a coefficient of variation of 10.18%. The mean hemoglobin concentration, by co-oximetry, was 5.014 mmol·L−1, coefficient of variation, 2.99%.Conclusion:This arrangement is a potential bedside method of estimating blood volume and circulating hemoglobin mass. We have rendered the technique more acceptable clinically by creating a ventilator-driven administration system.