A lipopolysaccharide (LPS) mutant (FA5100) of a serum-resistant strain of Neisseria gonorrhoeae (FA19) was found to be highly sensitive to the bactericidal activity of normal human serum (NHS). Both strain FA5100 and an unrelated serum-sensitive clinical isolate (F62) were killed by NHS via the classical complement pathway since killing required C2 and Ca⁺⁺. However, the fact that only strain FA5100 was sensitive to human hypogammaglobulinemic and cord serum suggested that this strain might activate the classical complement pathway in the absence of antibody. Anticomplementary concentrations of LPS from strain FA5100 inhibited the bactericidal activity of NHS against either strain FA5100 or strain F62. However, concentrations of LPS from strain FA5100 that exhibited marginal anticomplementary behavior also inhibited the killing of strain F62 by NHS. The ability of LPS from strain FA5100 to inhibit the bactericidal activity of NHS against strain FA5100 and to activate complement was reduced by treatment with mild alkali. However, alkali-treated LPS from strain FA5100 still inhibited the bactericidal activity of NHS against strain F62.