Sickle cell anemia (SCA) is a genetic disease which is characterized by painful episodes of vascular occlusions. In the present study, we investigated a potential contribution of the autonomic nervous system (ANS) in initiating such episodes. We observed prominent decreases in microvascular perfusion in response to spontaneous sighs, which may increase the likelihood of red blood cell polymerization followed by vascular occlusions in SCA patients. Time-varying spectral analysis of heart rate variability (HRV), based on recursive least squares estimation, was employed to study the modulation of the ANS in response to sighs. To improve robustness of the spectral estimation while retaining its ability to track rapid changes, we propose a time-varying parameter estimate variability reduction (TV-PEVR) technique. Because respiration patterns can vary considerably across subjects, we employed a time-varying autoregressive with exogenous input (TV-ARX) model to adjust for the effect of respiration patterns on the HRV indices. Results from 8 SCA subjects and 9 normal controls suggested that the cardiac ANS responses to sighs are not different between the two groups, after adjusting for the effect of post-sigh respiration. However, the peripheral sympathetic response in SCA appeared to be enhanced in this group relative to normals, and sighs may play a role in initiation of vaso-occlusive events in this group of patients.