Drug-resistant epilepsy (DRE) presents significant challenges in treatment and management. While seizure-related alterations in peripheral immune players are increasingly recognized, the involvement of the immune complement system remains insufficiently explored in DRE. We studied complement components and their relationship to cytokine profiles in serum samples from 46 DRE patients and 45 matched healthy controls. We examined relationships between these molecules and clinical outcomes, including epilepsy duration, intelligence scores, and age. We identified DRE-associated complement decreases, including reduced levels of C1q, Factor H, C4, C4b, C3, and C3b/iC3b, as well as elevated bFGF. DRE females showed dysregulation of the classical complement pathway and lower TNFα and interleukin-8 compared to healthy females. DRE males exhibited dysregulation of the classical, lectin, and terminal complement pathways, with trends of increased CCL2 and CCL5 compared to healthy males. Specific complement and inflammatory markers (C2, IL-8, and IL-9) correlated with full-scale IQ scores in DRE patients. Our study reveals significantly lower levels of circulating complement components in DRE and sex-specific complement dysregulation and cytokine imbalances. These findings suggest an underlying peripheral immune system vulnerability that may be sex-dependent and warrants further investigation in DRE.