Tests for cytomegalovirus (CMV) macroglobulin and complement-fixing antibody were performed on specimens of serum submitted for titers of heterophil-agglutinin. Of 43 heterophil-positive specimens, 42 were positive for CMV macroglobulin. In contrast, seven of 40 heterophil-negative and three of 50 normal control sera were macroglobulin-positive. The incidence and titers of complement-fixing antibody to CMV were not significantly different in heterophil-positive, negative, and normal controls. Of 105 patients with various diseases tested for CMV macroglobulin, 15 were macroglobulin-positive; nine of these had varicella-zoster infections and four had evidence of active CMV infection. These data suggest that CMV antigen cross-reacts with a macroglobulin in the serum of patients with other cell-associated herpesvirus infections.