Recent reports have described resistance to pancuronium-induced neuromuscular blockade in patients chronically receiving anticon-vulsants. This study examines the pharmacokinetics and pharma-codynamics of metocurine (MTC) in 12 patients undergoing cra-niotomy—six on chronic phenytoin therapy and six comparable controls. Each patient received MTC 0.2 mg/kg during the induction of general anesthesia. Quantification of plasma MTC concentration was performed by radioimmunoassay, while the response to MTC was evaluated by evoked compound electromyography (ECEMG). Patients in the phenytoin group were resistant to this dosage of MTC, as demonstrated by their response (83 ± 16% compared with 98 ± 2% depression of ECEMG in control patients,P< 0.05) and by recovery index, defined as the time required for recovery from 25 to 75% of the control ECEMG (53 ± 22 min compared with 125 ± 54 min in control patients,P< 0.01). Similarly, the total duration of neuromuscular blockade, measured to recovery to 90% of control ECEMG, was significantly shorter in the phenytoin group (122 ± 25 min compared with 269 ± 64 min in the control group,P< 0.01). Plasma concentration-time curves were fit to biexponential equations for both groups. These were used to generate two-compartment models. Neither the model parameters nor the plasma concentrations of MTC at any time in the study were significantly different for the two groups. The pharmacody-namic analysis, however, showed that patients on phenytoin require a higher plasma concentration of MTC (0.415 ± 0.095 μg/ml compared with 0.249 ± 0.066 μg/ml in control patients at 50% ECEMG,P< 0.01) to effect a given level of neuromuscular blockade. This resistance could be demonstrated at all levels of neuromuscular blockade (20–80% depression of ECEMG). On the basis of this study, it can be concluded that resistance to metocurine in patients chronically being treated with phenytoin does exist as a result of some, yet undefined, pharmacodynamic alteration in this patient group.