1. Although (+)-tubocurarine (Tc) is classically considered to be a competitive antagonist at the neuromuscular junction, kinetic details of the interaction remain unclear. 2. We studied the competitive action of Tc on the nicotinic receptor at the frog neuromuscular junction using a quantitative analysis of the generation phase of miniature endplate currents (m.e.p.cs) recorded in Ringer solution (20 degrees C) under voltage clamp (-90 mV) in the absence or presence of 1-5 microM Tc. Under control conditions four neurotransmission parameters were estimated by non-linear regression using a mathematical model of synaptic transmission incorporating transmitter release, diffusion, hydrolysis, receptor binding and channel gating. These parameters were then used in a further regression to estimate binding rate constants for Tc at the same endplate. Allowance was made for open channel block by Tc, which under the conditions of this study was only a small component of total blockade. 3. The results suggest that Tc binds to the two agonist recognition sites on the nicotinic receptor with equal affinity (stoichiometric KDs of 2.2 and 8.8 microM), and that most of the functional blockade at concentrations up to 5 microM is due to occupancy of only one site. 4. The association rate constant for Tc binding to sites on the nicotinic acetylcholine receptor appears to be very fast (k+D = 8.9 x 10(8) M-1 s-1) and comparable to that for acetylcholine (ACh). 5. In the brief time during which an m.e.p.c. is generated (approximately 200 microseconds, reversal of Tc blockade by transiently high concentrations of ACh seems to be kinetically limited.