The role of neutrophil complement receptors in the opsonophagocytosis of 10 strains of coagulase-negative staphylococci was investigated. Polymorphonuclear leukocytes from adults as well as term and premature newborn infants were tested with normal human serum, adult hypogammaglobulinemic serum, and pooled premature infant serum in an opsonophagocytic assay. Neutrophils from premature infants demonstrated significantly lower killing capacity (62%) than neutrophils from adults (86%) or term infants (84%; P less than 0.02). Maximum inhibition of opsonophagocytosis by adult or infant neutrophils occurred with an FcIII receptor blockade (80%), whereas a blockade of complement receptors produced minimal inhibition. Opsonophagocytic activity for the coagulase-negative staphylococci was not influenced by the serum source but was influenced by reducing the serum concentration below 5%. Abrogation of the complement activity of normal human serum by heating or the addition of ethylenediamine tetraacetate reduced opsonophagocytosis by 100 and 96%, respectively, whereas selective inhibition of the classical complement pathway reduced opsonophagocytosis by only 40%. Thus, opsonophagocytosis of coagulase-negative staphylococci by human sera appears to be mediated primarily by neutrophil Fc receptors, but complement is also required. The inefficiency of these interactions with neutrophils from premature infants may partially explain the enhanced susceptibility of very-low-birth-weight neonates to disseminated, coagulase-negative staphylococcal infections.