BackgroundElectrical nerve conduction block has great potential for treatment of disease through reversible and local inactivation of somatic and autonomic nerves. However, the relatively high energy requirements and the presence of undesired excitation at the onset of the kilohertz-frequency (KHF) signals used for block pose obstacles to effective translation. Frequency, electrode geometry, and waveform shape are known to influence block threshold and onset response, but available data provide a limited understanding of how to select these parameters to optimize nerve block.MethodsWe evaluated KHF nerve block in rat tibial nerve across frequencies (5–60 kHz), electrode geometries (monopolar, bipolar, and tripolar), and waveform shapes. We present a novel Fourier-based method for constructing composite signals that systematically sample the KHF waveform design space.ResultsThe lowest frequencies capable of blocking (5–16 kHz) were not the most energy-efficient among the tested frequencies. Further, bipolar cuffs required the largest current and power to block, monopolar cuffs required the lowest current, and both tripolar and monopolar cuffs required the lowest power. Tripolar cuffs produced the smallest onset response across frequencies. Composite signals comprised of a first harmonic sinusoid at fundamental frequency (f0) superposed on a second harmonic sinusoid at 2f0could block at lower threshold and lower onset response compared to the constituent sinusoids alone. This effect was strongly dependent on the phase of the second harmonic and on the relative amplitudes of the first and second harmonics. This effect was also dependent on electrode geometry: monopolar and tripolar cuffs showed clear composite signal effects in most experiments; bipolar cuffs showed no clear effects in most experiments.ConclusionsOur data provide novel information about block threshold and onset response at the boundary of frequencies that can block. Our results also show an interaction between spatial (cuff geometry) and temporal (frequency and waveform shape) parameters. Finally, while previous studies suggested that temporal parameters could reduce onset response only in exchange for increased block threshold (or vice versa), our results show that waveform shape influences KHF response in ways that can be exploited to reducebothenergy and onset responses.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12984-023-01195-8.