The ability of various fragments of human myeloma IgG1 to inhibit rosette formation between human anti-D-coated human red blood cells and human polymorphonuclear leukocytes has been investigated. Although IgG and Fc showed a dose-dependent inhibition of rosettes at equimolar concentrations, neither of the fragments corresponding to the Cγ2 and Cγ3 homology regions obtained by acid-tryptic cleavage of Fc was able to inhibit rosette formation. The pepsin fragment of Fc, pFc′, which represents the complete Cγ3 domain, was also unable to prevent rosette formation. Reduction and alkylation of IgG or Fc markedly diminished cytophilic activity as measured by this system. These data indicate that the site in human IgG1 bound by granulocytes is dependent on the full quaternary structure of Fc, a requirement in marked contrast to that noted for binding by macrophages and monocytes.