The plasma protein binding of bupivacaine in heparinized plasma from healthy volunteers and patients receiving diphenylhydantoin, quinidine or pethidine was investigated using equilibrium dialysis technique at 4°C. The mean unbound fraction in normal individuals was 6.3 ±0.68 (SEM) percent at a concentration of 1 μg/ml. The percent binding was decreased as the drug concentration increased. There was an increase of 300–400% unbound bupivacaine in plasma taken from patients. The addition of diphenylhydantoin, quinidine, pethidine, desipramine, but not atropine, to normal plasma also caused marked displacement of bupivacaine. If this effect occurs in vivo, the likelihood of increased local anaesthetic toxicity may be increased.