Novel therapeutic targets are required to develop new treatments to lower the rates of drug-resistant epilepsy (DRE). This study assessed differences in plasma inflammatory biomarker concentrations and monocyte phenotype and function in patients with DRE versus psychogenic non-epileptic seizures (PNES). Luminex was used to analyse plasma samples from 21 DRE cases and 19 PNES controls for concentrations of selected cytokines and chitinase 3-like 1 (CHI3L1). Flow cytometry was used to quantify the percentage of monocytes expressing HLADR, CD14, CD16, CD11b, P2X7R and their median fluorescence intensity (MFI) ratio in 22 DRE and 11 PNES patients. Flow cytometry was used to assess P2X7 receptor (P2X7R) pore function via YO-PRO-1 uptake. No difference in cytokine and CHI3L1 concentrations was seen. Compared to PNES, DRE had a higher percentage of 'classical' monocytes (CD14++CD16-) and less 'non-classical' monocytes (CD14-CD16+). The percentage of 'classical' monocytes expressing P2X7R was increased in DRE compared to PNES. CD11b MFI ratio was increased in 'classical' and 'intermediate' (CD14+CD16+) monocytes. P2X7R pore function was similar between groups. Overall, while cytokine levels were similar between groups, the differences in monocyte phenotype indicates a more 'proinflammatory' circulating innate immune state in DRE. Thus, monocytes may be a novel therapeutic target for future research.