BACKGROUND: The aim of this study was to compare the incidence of arterial hypotension in response to autologous blood donation with and without simultaneous IV fluid replacement in 60 patients with cardiovascular disease. STUDY DESIGN AND METHODS: Each patient donated two 500 mL units of blood at an interval of 7 days. Following random allocation within a two-stage crossover design, either the first or second unit was collected with a simultaneous IV infusion of 500 mL of HES. Patients receiving IV fluid replacement during their first donation did not receive any fluid replacement during their second donation and vice versa. Starting before phlebotomy, arterial blood pressure was measured oscillometrically every 5 minutes until 30 minutes after donation. Hypotension was defined as at least one decrease of more than 20 percent from baseline in systolic blood pressure. RESULTS: A decrease of more than 20 percent from baseline in systolic blood pressure occurred in 2 of the 60 patients (3%) during the donations with IV fluid replacement compared with 55 of the 60 patients (92%) during the donations without IV fluid replacement (p < 0.0001, McNemar's test). No severe reaction to blood donation was observed in any patient, regardless of whether IV fluids had been administered. CONCLUSION: Isovolemic IV fluid replacement was useful in preventing arterial hypotension in autologous blood donors with cardiovascular disease. Its effect on the safety of the autologous blood donation process remains to be established.