We show that dimerization of major histocompatibility complex (MHC) class I on a human monocytic cell line, THP-1, induces nitric oxide (NO) synthesis. Cells cultured in the presence of a human MHC class I-specific monoclonal antibody produced significant amounts of NO after 72 hr. Reverse transcription-polymerase chain reaction and flow cytometry analysis revealed that the cells synthesized detectable levels of inducible NO synthase mRNA and protein. These effects were not seen after treatment with monovalent Fab fragments or Fc fragments of the same antibody, or after treatment with a control antibody. These data show a link between innate and acquired immune mechanisms mediated by NO and MHC class I.