<i>Objective:</i> Recent data suggest that vagus nerve stimulation (VNS) can inhibit cytokine release by inflammatory cells. Accordingly, an association between impaired cardiac parasympathetic function, as assessed by heart rate variability (HRV), and increased markers of inflammation has recently been reported. In this study we assessed the effect of direct left VNS on inflammatory markers and HRV in patients with refractory epilepsy. <i>Methods:</i> A 24-hour electrocardiogram Holter recording was performed both at baseline and after 3 months of left VNS in 8 patients (age 32 ± 24 years, 2 men) who underwent implantation of a VNS device because of refractory epilepsy. Tumor necrosis factor-α, interleukin-6 and C-reactive protein serum levels were measured, as markers of inflammation, at the same times. <i>Results:</i> No significant changes were found after 3 months of left VNS, compared to baseline, both for HRV variables and inflammatory markers. Also, no consistent correlation could be demonstrated between HRV parameters and inflammatory markers in these patients. <i>Conclusions:</i> Our data in epileptic patients without cardiovascular disease failed to show a significant effect of left VNS on cardiac autonomic function and on systemic inflammation at short-term follow-up.