The effects on neuromuscular (NM) function of combinations of relaxants (d-tubocurarine, pancuronium, and succinylcholine) and local anesthetics (cocaine, procaine, lidocaine, etidocaine, and a quaternized derivative of procaine, procaine methobromide) were investigated using the rat's phrenic nerve-hemidiaphragm preparation. Combinations of ineffective concentrations of NM blocking agents with ineffective concentrations of local anesthetics caused a greater than 90% NM block. Preliminary administration of ineffective concentrations of local anesthetics significantly (p <0.001) decreased the ED50 or NM blocking agents. The administration of ineffective concentrations of NM blocking agents caused a similar decrease of the ED50 of local anesthetics. Concentrations of d-tubocurarine and pancuronium which alone produced partial NM block had additive effects. These findings suggest that the interaction of NM blocking agents and local anesthetics consists of true potentiation caused by the different sites of action of the two types of compounds at the NM junction. The degree of potentiation may be enough to cause clinically significant NM block in patients who at the same time receive high enough doses of both agents. In vitro the NM block caused by the combinations of local anesthetics and NM blocking agents can be reversed by 4-aminopyridine.