The time course of changes in brain electrical activity during halothane anesthesia was examined in 12 malignant hyperthermiasusceptible (MHS) and 14 normal (nMHS) swine. Power densities in selected frequency bands were calculated from the electroencephalogram (EEG). EEG and systemic variables were determined over a period of 60 min after starting halothane (1% inspired). Malignant hyperthermia (MH) was triggered in all susceptible pigs. Initial changes in the EEG during development of MH consisted of a decrease in total power and a shift to lower frequencies (deltatheta activity) in all animals. These EEG alterations were noted when there was an increase in heart rate, but other systemic variables were still normal. EEG changes in all MHS animals started at an arterial oxygen tension (Pao2) greater than 90 mmHg and an arterial carbon dioxide tension (Paco2) less than 50 mmHg. In 5 MHS animals EEG became isoelectric at a Pao2of 61–82 mmHg and a Paco2of 53–68 mmHg. Mean arterial blood pressure at this time was 54–66 mmHg. To determine the effects of hypoxia on the EEG in 7 nMHS animals, oxygen was decreased over a period of 45–60 min to 7% inspired. In 7 other nMHS animals, hypercarbia was produced by admixture of carbon dioxide to the fresh gas supply to achieve incremental increases of Paco2to 110–120 mmHg. Significant EEG changes during hypoxia comparable to those seen at the onset of MH were noted at a Pao2below 40 mmHg and during hypercarbia at a Paco2greater than 68 mmHg. Our results do not support the hypothesis that early EEG changes during MH occur as a result of systemic hypotension, hypoxemia, or hypercarbia.