The roles of Cl-dependent synaptic inhibition in the generation of fictive breathing were tested in isolated brains of adult lampreys, Ichthyomyzon unicuspis. Only a few inhibitory synaptic potentials were recorded in respiratory motoneurons between excitatory bursts. This was also true after Cl- injections inverted them to depolarizing potentials. A weak and variable phase of Cl-sensitive synaptic inhibition occurred at the ends of excitatory bursts. Respiratory motoneurons had a pronounced post-spike hyperpolarization, which was distinct from synaptic inhibition and appeared to be a more important mechanism for termination of firing. The production of the basic rhythm for respiration was tested in strychnine, picrotoxin, bicuculline and Cl-free fluid. Low concentrations of the blocking drugs prevented the inhibitory effects of bath-applied glycine and gamma-aminobutyric acid, but essentially normal respiratory bursts still occurred. Equilibration of isolated brains in high concentrations of strychnine and picrotoxin did not prevent periodic activities, but burst durations were increased and inter-burst intervals were longer and less regular than normal. Similar bursts could also occur transiently in Cl-free fluid. Recordings from the IX and X motor nuclei indicated that respiratory neurons produced the periodic bursts in the presence of strychnine and picrotoxin. Hemisections of the brain behind the V motor nuclei eliminated the bursts ipsilaterally. This indicated that descending excitation was necessary during pattern generation both in normal fluid and in the presence of antagonists of synaptic inhibition. Conventional synaptic inhibition does not appear to be essential for respiratory pattern generation in the adult lamprey but may contribute to its modulation. The hypothetical neural oscillator may consist of excitatory bursting interneurons.