We studied the use of physiologically based, multisite, intrafascicular electrical stimulation of the sciatic nerve to achieve ripple-free contractions and sustained, fatigue-resistant forces over a physiological range of forces in cat gastrocnemius muscle. Electrode arrays containing 100, 0.5-1.5-mm-long penetrating microelectrodes were inserted into the sciatic nerves of cats, and forces generated by gastrocnemius muscles in response to stimulation of the nerves were monitored via a force transducer attached to the tendons. In single-electrode stimulation, responses evoked by low-frequency [15 pulses/second, (p/s)] stimulation exhibited greater fatigue resistance than did responses evoked by higher frequency stimulation (30 and 60 p/s), but showed far more ripple within each response. We compared interleaved 15 p/s stimulation of four electrodes (100 micros biphasic pulses, 750-ms pulse trains) that produced a net stimulation frequency of 60 p/s with multielectrode 60 p/s quasi-simultaneous stimulation protocols. Across a broad range of forces (10% to 80% of maximum), responses evoked by multielectrode 15 p/s interleaved stimulation exhibited substantially less fatigue than did responses evoked by 60 p/s quasi-simultaneous stimulation, and less ripple than responses evoked by single-electrode 15 p/s stimulation. The effectiveness of this physiologically based stimulation paradigm encourages its application in the field of motor neuroprosthetics.