The lipopolysaccharide (LPS) of serum-sensitive strains of Escherichia coli was compared with LPS derived from serum-resistant clones. Polysaccharide O-antigen side chains (PSSC) of LPS from serum-resistant clones contained 12%-40% more of the longer carbohydrate molecules (L-PSSC) than did LPS from serum-sensitive parent strains; in contrast, 12%-27% more of the shorter PSSC (S-PSSC) were found in LPS from serum-sensitive strains. The sensitivity or resistance to the bactericidal activity of human serum correlated with the distribution and the length of PSSC fractions of LPS. This was demonstrated in a liposome model in which LPS was incorporated into simulated bacterial membranes. The incubation of serum with liposomes incorporated with various ratios of S-PSSC-to-L-PSSC concentrations resulted in liposomal lysis at S-PSSC-to-L-PSSC ratios >2:1. These findings demonstrate the importance of the length of carbohydrate side chains of LPS in determining sensitivity or resistance to the bactericidal activity of human serum.