Transcranial motor evoked potentials (TcMEPs) monitor the integrity of the spinal cord during spine surgery. Propofol-based anesthesia is favored in order to enhance TcMEP quality. During intraoperative hemorrhage, TcMEP amplitudes may be reduced. The serum concentration of propofol may increase during hemorrhage. No study has determined whether changes in TcMEPs due to hemorrhage are related to changes in propofol blood levels. We monitored TcMEPs, mean arterial pressure (MAP), and cardiac output (CO) and hemoglobin in pigs (n = 6) undergoing controlled progressive hemorrhage during a standardized anesthetic with infusions of propofol, ketamine, and fentanyl. We recorded TcMEPs from the rectus femoris (RF) and tibialis anterior (TA) muscles bilaterally. A pulmonary artery catheter was placed to measure CO. Progressive hemorrhage of 10% blood volume increments was done until TcMEP amplitude decreased by >60% from baseline. Serum propofol levels were also measured following removal of each 10% blood volume increment. TcMEP responses were elicited every 3 min using constant stimulation parameters. We removed between 20 and 50% of total blood volume in order to achieve the >60% reduction in TcMEP amplitude. MAP and CO decreased significantly from baseline. At maximum hemorrhage, TcMEP amplitude decreased in the RF and TA by an average of 73 and 62% respectively from baseline (P < 0.01). Serum propofol levels varied greatly among animals at baseline (range 410-1720 ng/mL) and increased in each animal during hemorrhage. The mean propofol concentration rose from 1190 ± 530 to 2483 ± 968 ng/mL (P < 0.01). The increased propofol concentration correlated with decreased CO. Multivariate analysis using hierarchical linear models indicated that the decline of TcMEP amplitude was primarily associated with rising propofol concentrations, but was also independently affected by reduced CO. We believe that the decrease in blood volume and CO during hemorrhage increased the serum concentration of propofol by reducing the volume of distribution and/or rate of hepatic metabolism of the drug. Despite wide acceptance of propofol as the preferred anesthetic when using TcMEPs, intravenous anesthetics are vulnerable to altered pharmacokinetics during conditions of hemorrhage and could contribute to false-positive TcMEP changes.