Alterations in red blood cell deformability (RBC-df) provide important information for the diagnosis of various diseases. We evaluated individual differences of lipopolysaccharide (LPS)-induced oxidative damage of RBC-df and analyzed the correlation between RBC-df and biochemical parameters. A microfluidic chip was developed to detect inter-individual variability of different concentrations of LPS-induced oxidative damage of RBC-df in 9 healthy volunteers. The relationships between various biochemical indicators (Na+-K+-ATPase activity, lipid peroxide (LPO) content, glutathione peroxidase (GSH-PX) activity, catalase (CAT) activity, superoxide dismutase (SOD) activity, adenosine triphosphate (ATP) content, and hemoglobin (HB) content) and RBCsdf were investigated. The obvious inter-individual variability of LPS-induced oxidative damage of RBC-df was revealed. The Na+-K+-ATPase activity, LPO content, GSH-PX activity, and CAT activity of RBCs showed significant correlations with RBC-df (P < 0.05). Oxidative damage and energy metabolism are the critical factors of RBC-df impairment induced by LPS, and the individual dependence on RBC-df is an important indicator for the treatment of infection-associated sepsis since antibiotics can kill pathogenic bacteria, which results in the release of LPS from the cell wall.