OBJECTIVE: Clinical indexes of autonomic activity are based on the analysis of sinus cycle length and of its variability. A common assumption underlying this practice is that neural activity and cycle length may be linearly related. Recent experimental evidence suggests that such an assumption may not be correct; indeed, the relation linking autonomic agonist concentration to cycle length was found to be strongly non-linear in single sinoatrial myocytes. In the present work, we (i) test compatibility of non-linearity of neural modulation of cycle length (CL) with previous experimental and clinical observations; (ii) evaluate its implications for what concerns the interpretation of time- and frequency-domain parameters of heart rate variability (HRV) and baroreflex sensitivity (BRS). CONCLUSION: Non-linearity of neural modulation of CL may result in an intrinsic rate-dependency of autonomic indexes, with the exception of normalised frequency-domain indexes (e.g. the low frequency/high frequency (LF/HF) ratio), which appear to be devoid of intrinsic rate-dependency. This characteristic may not limit the value of HRV indexes and BRS in risk stratification, but has to be taken into account in their pathophysiological interpretation.