A comparison was made of neuromuscular junctions in cutaneous pectoris and cutaneous dorsi muscles of Rana pipiens in order to study mechanisms controlling synaptic efficacy. Other than a small difference in junctional size, the two muscles were structurally and functionally very similar. Despite these similarities, cutaneous pectoris junctions had substantially higher synaptic safety margins. With intracellular recording, it was apparent that the difference in safety margin was due to a large difference in transmitter release. In low-Ca2+ solutions, levels of evoked and spontaneous release were 4 times higher in the cutaneous pectoris. When corrected for differences in nerve terminal size at identified junctions, there remained a 3-fold difference in evoked release and a 6-fold difference in spontaneous release per unit terminal length. Differences in normal Ringer solution were 1.8- and 2.5-fold for evoked and spontaneous release, respectively. There was no simple relationship between synaptic efficacy and the total amount of nerve terminal supported by each motoneurone in different frog muscles. We concluded that there can be large differences in synaptic efficacy without correlated structural differences visible with the light microscope.