A generalized proinflammatory state has been observed in individuals with panic disorder (PD). There is evidence that slow-paced breathing (SPB) with heart rate variability-biofeedback (HRV-BF) strengthens the nervus vagus with its anti-inflammatory pathway. Therefore, with this randomized controlled trial we aimed to investigate the effect of a four-week SPB with HRV-BF intervention on pro-inflammatory cytokines in people with PD. Fifty-five individuals with PD (mean age: 37.22 +/- 15.13 years) were randomly allocated either to SPB-HRV-BF (intervention group) or to HRV-Sham-BF (active control group). SPB-HRV-BF was performed over four weeks while cytokine concentration and HRV during a short-term resting condition were measured before and after intervention. SPB-HRV-BF decreased concentration of Tumor Necrosis Factor alpha (TNF-alpha) (F((1, 53)) = 4.396, p </= .05, eta2 = 0.077) in individuals with PD. In addition, SPB-HRV-BF demonstrated an increase in the HRV-time and frequency domain parameters SDNN, Total Power and LF during short-term resting condition. There was no intervention effect in HRV-Sham-BF group. In conclusion, SBP-HRV-BF as a non-pharmacological treatment may reduce pro-inflammatory cytokine TNF-alpha via the cholinergic anti-inflammatory pathway in individuals with PD. Based on the generalized proinflammatory state in PD, decreasing TNF-alpha is highly beneficial to reduce risk of cardiovascular diseases and metabolic syndrome.