Epstein-Barr-virus (EBV)-induced infectious mononucleosis usually occurs in young adults between the ages of 15 and 30. When it occurs in older individuals, it frequently presents diagnostic problems. This report describes data from 27 such patients aged 40 to 72, all of whom had definitive evidence of a current EBV primary infection. Protracted fever, jaundice, pleural effusion, anemia, or the Guillain-Barré syndrome were dominant clinical findings among these patients. Fourteen patients were hospitalized and numerous diagnostic procedures were performed, including bone-marrow aspirations (8 patients), abdominal CAT scan procedures (4 patients), and liver (2 patients) or lymph-node biopsies (1 patient). Overall, the laboratory data in these patients were similar to those seen in young adults, with the exception of more marked hepatic dysfunction and more prominent antibody responses to the restricted (R) component of the early antigen complex. Particularly difficult were the diagnostic problems encountered in three patients in this study (3/27) who failed to develop heterophil antibodies.