Pretreatment with cyclosporine reportedly prolongs the effect of certain general anesthetics in humans and the sleeping time of mice after pentobarbital administration. This investigation was designed to determine the mechanism(s) of the cyclosporine–barbiturate interaction. Adult female Wistar rats received cyclosporine (50 mg/kg im) or saline solution daily for 3 days. On the third day, they were injected with heptabarbital (45 mg/kg iv). Other cyclosporine‐treated and control groups were infused with heptabarbital until they lost their righting reflex. Treatment for 3 d with cyclosporine was associated with decreased rectal temperature, decreased magnesium concentrations in serum and CSF, increased serum creatinine and urea nitrogen concentrations, elevated serum aspartate aminotransferase activity and total bilirubin concentration, decreased serum total protein concentration, and increased hematocrit. These physiologic changes are consistent with the clinically observed hypomagnesemia, nephrotoxicity, and hepatotoxicity in patients treated with cyclosporine. Control rats slept for 90 ± 14 min (mean ± SD, n = 9) after heptabarbital injection, whereas cyclosporine‐pretreated rats slept for 154 ± 22 min. Compared with controls, cyclosporine‐pretreated rats awoke (after heptabarbital injection) and went to sleep (after heptabarbital infusion) with significantly lower barbiturate concentrations in serum and CSF. Pretreatment with a single 60‐mg/kg im dose of cyclosporine 2 h before heptabarbital infusion caused no significant biochemical changes ∼ 160 min later, except for elevated serum aspartate aminotransferase (which occurred also after injection of the surfactant‐containing vehicle) and serum bilirubin. Again, heptabarbital concentrations at onset of sleep (loss of righting reflex) in serum, brain, and CSF of cyclosporine‐treated rats were significantly lower than in saline‐treated controls. Two or three days of pretreatment with cyclosporine (50 mg/kg/day, im) had no significant effect on the total clearance of the barbiturate. These results indicate that cyclosporine can prolong barbiturate‐induced general anesthesia by a pharmacodynamic mechanism.