A bionic baroreflex system (BBS) is a computer-assisted intelligent feedback system to control arterial pressure (AP) for the treatment of baroreflex failure. To apply this system clinically, an appropriate efferent neural (sympathetic vasomotor) interface has to be explored. We examined if the spinal cord is a candidate site for such interface. In 6 anesthetized and baroreflex deafferentiated cats, a multi-electrode catheter was inserted into the epidural space to deliver epidural spinal cord stimulation (ESCS). Stepwise changes in ESCS rate revealed a linear correlation between ESCS rate and AP at stimulation rates of 2 pulse/sec and above (r², 0.876-0.979; slope, 14.3±5.8 mmHg/[pulse/sec]; pressure axis intercept, 35.7±25.9 mmHg). Random changes in ESCS rate with a white noise sequence revealed dynamic transfer function of peripheral effectors. The transfer function resembled a second-order low-pass filter with a lag time (gain, 16.7±8.3 mmHg/[pulse/sec]; natural frequency, 0.022±0.007 Hz; damping coefficient, 2.40±1.07; lag time, 1.06±0.41 sec). Based on the transfer function, we designed an artificial vasomotor center to attenuate hypotension. We evaluated the performance of the BBS against hypotension induced by 60° head-up tilt (HUT). In the cats with baroreflex failure, HUT dropped AP by 37±5 mmHg in 5 sec and 59±11 mmHg in 30 sec. BBS with optimized feedback parameters attenuated hypotension to 21±2 mmHg in 5 sec (p<0.05) and 8±4 mmHg in 30 sec (p<0.05). These results indicate that ESCS-mediated BBS prevents orthostatic hypotension. Since epidural stimulation is a clinically feasible procedure, this BBS can be applied clinically to combat hypotension associated with various pathophysiologies.