The effects of primidone (1.0 mM), phenobarbital (0.2 mM) and phenylethylmalonamide (PEMA) (1.0 mM) on nerve-stimulated transmitter release (quantal content) were determined for extracellular Ca++ concentrations ([Ca++]0) from 0.4 to 0.8 mM at 1.0 Hz nerve stimulation frequency. At these [Ca++]0, the relationship between the log of quantal content vs. the log of [Ca++]0 is linear. Both primidone and phenobarbital increased quantal content to 171% of controls. These drugs, however, caused parallel shifts of the log-log plot of quantal content vs. [Ca++]0 to the left. Thus, drug effects were not modified by varying [Ca++]0. These drugs were also examined on frequency facilitation. During frequency facilitation, the relationship between the log of quantal content vs. nerve-stimulation frequency (0.5-8.0 Hz) is linear. Both primidone and phenobarbital caused parallel shifts of this plot to the left. These drug effects, therefore, were not modified by nerve stimulation frequency. PEMA did not affect quantal content in either series of experiments. Finally, the sciatic nerve was not stimulated and spontaneous transmitter release was measured. Under these conditions, phenobarbital increased transmitter release in high external K+ (7.5 mM) (1.8 mM Ca++, no Mg++) and in normal K+ (2.5 mM) (1.8 mM Ca++, no Mg++) to the same magnitude (130% of control) in contrast to the reported effects of primidone and PEMA. In conclusion, the effects of primidone, phenobarbital and PEMA were different in the stimulated frog neuromuscular junction.