The influence of hyperkalemia on the central nervous system and cardiac toxicity of bupivacaine and lidocaine was studied in open-chested mechanically ventilated dogs. The seizure and cardiotoxic doses of intravenously administered lidocaine and bupivacaine were determined in two separate groups of normokalemic (2.7 · 0.05 SEM mEq/1) dogs. In the case of both anesthetics, the cardiotoxic dose was found to be approximately four times the seizure dose. Under conditions of hyperkalemia (5.4 · 0.08 SEM mEq/1), however, the cardiotoxic doses of both anesthetics were decreased significantly to approximately two times the seizure dose. Hyperkalemia did not change the seizure dose for either anesthetic. The cardiac to seizure dose ratio was decreased significantly for bupivacaine but not for lidocaine. The results of this study suggest that hyperkalemia enhances the cardiotoxic effects of both lidocaine and bupivacaine, with this enhancement being more pronounced in the case of bupivacaine.