BACKGROUND: We recently described an association between reduced heart rate variability (HRV) and illness burden in bipolar disorder (BD) using a novel Illness Burden Index (IBI). We aimed to further characterize this association by using spectral analyses to assess whether the IBI is also associated with autonomic imbalance in BD patients. METHODS: In this cross-sectional study, 53 participants with BD wore a device for 24 h to assess association between HRV spectral measures and the IBI or each of its components (age of onset, number and type of previous episode(s), duration of the most severe episode, history of suicide attempts or psychotic symptoms during episodes, co-morbid psychiatric disorders, and family history). We ran both unadjusted models and models controlling for age, sex, years of education, marital status, BMI, pharmacotherapy, and baseline functional cardiovascular capacity. RESULTS: HRV low-frequency (LF) normalized values were almost twice as high as published in healthy controls. Higher IBI was associated with higher LF and lower High Frequency (HF) values, resulting in a higher LF/HF ratio, indicating an increased sympathetic tone. Four individual components of the IBI were similarly associated with measures of increased sympathetic tone: earlier age of onset, number of depressive episodes, co-morbid anxiety disorders, and family history of suicide. Adjusted and unadjusted models had similar results. LIMITATIONS: Our models used mean LF and HF and do not consider their dynamic variations over 24 h or phase of the illness. CONCLUSIONS: Burden of illness is associated with increased sympathetic tone in patients with BD, putting them at risk for arrythmias and sudden death.