Pro-inflammatory factors may be associated with abnormalities in functional brain networks, which may be a mechanism in the pathogenesis of major depressive disorder (MDD). Electroencephalogram (EEG) microstates reflect the functioning of brain networks. However, the relationship between pro-inflammatory factors and the microstate abnormalities in patients with MDD is poorly understood. 24 MDD patients and 24 age-and sex-matched healthy controls (HC) were recruited. Montgomery-Asberg Depression Rating Scale(MADRS) were assessed. Serum (interleukin- 2(IL- 2), tumor necrosis factor-α (TNF-α) and hs-C-reactive protein (CRP)and EEG data were collected. K-means clustering was performed to characterize different microstates. For each microstate, duration, occurrence and coverage were estimated. Four microstates (e.g. A, B, C, D) were characterized, MDD group showed lower duration, occurrence and coverage of microstate B and microstate D, while higher duration of microstate A and microstate C and levels of IL-2, TNF-α, hs-CRP than HC group. The duration, occurrence and coverage of microstate D were negatively correlated with levels of pro-inflammatory factors (IL-2, TNF- α and hs- CRP) (all P < 0.05). Serum pro-inflammatory induced the abnormalities of microstate D. Together, these findings add to the understanding of the pathophysiology of MDD and point to pro-inflammatory factors contribute to EEG microstate abnormalities in patients with MDD.© 2022 The Authors.