Heart rate (HR) power spectral indices are limited as measures of the cardiac autonomic nervous systems (CANS) in that they neither offer an effective marker of the -sympathetic nervous system (SNS) due to its overlap with the parasympathetic nervous system (PNS) in the low frequency (LF) band nor afford specific measures of the CANS due to input contributions to HR (e.g., arterial blood pressure (ABP), instantaneous lung volume (ILV)). We derived new PNS and SNS indices by multi-signal analysis of cardio-respiratory variability. The basic idea is to identify the autonomically mediated transfer functions relating fluctuations in ILV to HR (ILVHR) and fluctuations in ABP to HR (ABPHR) so as to eliminate the input contributions to HR and then separate each estimated transfer function in the time domain into PNS and SNS indices using physiologic knowledge. We evaluated these indices with respect to selective pharmacological autonomic nervous blockade in 14 humans. Our results showed that the PNS index derived from the ABPHR transfer function was correctly decreased after vagal and double (vagal+-sympathetic) blockade (p<0.01) and did not change after -sympathetic blockade, while the SNS index derived from the same transfer function was correctly reduced after -sympathetic blockade in the standing posture and double blockade (p<0.05) and remained the same after vagal blockade. However, this SNS index did not significantly decrease after -sympathetic blockade in the supine posture. Overall, these predictions were better than those provided by the traditional high frequency (HF) power, LF/HF ratio, and normalized LF power of HR variability.