Studies show negative correlations between heart rate variability (HRV) and inflammatory markers. In cardiac patients, depression is related to both. We investigated links between short-term HRV and inflammatory markers in relation to depression in acute coronary syndrome (ACS) patients. We measured C-reactive protein (CRP), interleukin-6 (IL-6), depression symptoms (Beck Depression Inventory, BDI-II), and SDNN, high frequency (HF) and low frequency (LF) power at rest in 682 (553 men) patients approximately two months post-ACS. There were no differences in HRV measures between those with and without elevated depressions symptoms (BDI-II >or= 14). However, all HRV measures were negatively and significantly associated with both inflammatory markers. Relationships were stronger in patients with BDI-II >or= 14. Differences were significant for CRP and not explained by covariates (including age, sex, previous MI, left ventricular ejection fraction, coronary bypass surgery at index admission, diabetes, smoking, body mass index (BMI), fasting cholesterol, fasting glucose, angiotensin-converting-enzyme inhibitors, beta-blockers, statins, and antidepressants). HRV independently accounted for at least 4% of the variance in CRP in the depressed, more than any factor except BMI. Relationships between measures of inflammation and autonomic function are stronger among depressed than non-depressed cardiac patients. Interventions targeting regulation of both autonomic control and inflammation may be of particular importance.