In-vitro studies revealed that normal human serum contains factors that are lethal for L-phase variants of certain gram-negative and gram-positive bacteria. Killing of L-phase variants by normal human serum was very rapid and, as revealed by electron microscopic studies, was accompanied by lysis and fragmentation of the cytoplasmic membrane. The factors responsible for the lethal action of serum appear to be complement and specific immunoglobulin (IgG, IgM, or both, depending on the species of the L-phase variant being killed). If this serum system is active in vivo, it may influence significantly the role of certain L-phase variants in infectious diseases of man.