Numerous studies have documented a significant association between symptom severity and cognitive functioning in bipolar disorder (BD). These findings advanced speculations about a potential link between the physiological stress associated with illness severity and cognitive dysfunction. To explore this hypothesis, the current study employed heart rate variability (HRV) as a physiological measure that is sensitive to the effects of chronic stress, and a scale of trait anxiety for assessing a psychological condition that is correlated with hyper sympathetic arousal. Analyses indicated that BD patients with High Illness Severity reported more symptoms of trait-anxiety (i.e., State Trait Anxiety Inventory), performed more poorly on a computerized neuropsychological battery (i.e., CNS Vital Signs), and exhibited a more constricted HRV profile (i.e., lower SDNN with elevated LF/HF ratio) than patients with Low Illness Severity. Illness severity was determined by a history of psychosis, illness duration, and number of mood episodes. A third group of healthy controls (n=22) performed better on the neuropsychological battery and exhibited a healthier HRV profile than the BD groups. This study provides preliminary evidence that illness severity and cognitive impairment in BD may be associated with state anxiety and neuro-cardiac alterations that are sensitive to physiological stress.