A 75-year-old woman presented with altered mental status, septic picture, and influenza-like symptoms. Initial investigations revealed atypical lymphocytosis, thrombocytopenia, elevated liver enzymes, and a positive monospot test result. Further investigation showed the Epstein-Barr virus viral capsid antibody IgM/IgG and Epstein-Barr virus DNA by polymerase chain reaction to be negative; however, interestingly her cytomegalovirus (CMV) IgM and IgG were positive, suggesting that her mononucleosis-like syndrome was due to acute CMV infection. Herein, we report the first case of a heterophile-positive mononucleosis syndrome caused by acute CMV infection in an elderly immunocompetent woman. This case conveys that monospot test can yield false-positive result in the setting of acute CMV infection.