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Epstein-Barr virus (EBV), cytomegalovirus (CMV), and Mycoplasma pneumoniae are common pathogens of respiratory infection among children and young adults. Although single infection of 1 of these pathogens is common enough, their coinfection has been rarely reported. A 19-year-old woman presented with severe upper abdominal pain for 5 hours as well as flu-like symptoms and jaundice for 2 to 3 weeks. Initial tests found pancytopenia, abnormal liver functions, and presence of atypical lymphocytes in blood smear; the computed tomography of the abdomen revealed para-aortic lymphadenopathy, splenomegaly, and a wedge-shaped focal hypodensity lesion at the periphery of the spleen that was later diagnosed as splenic infarction. Her presentation raised suspicion of infectious mononucleosis. Nevertheless, monospot test, human immunodeficiency virus screening, and hepatitis viral serology were all negative, except that her M pneumoniae immunoglobulin M was found positive. Azithromycin was promptly given, but her fever and abdominal pain persisted. A strong suspicion of mononucleosis led to serological tests for EBV and CMV, which confirmed coinfection of EBV and CMV. By hospital day 7, her fever and abdominal pain had subsided and her liver function became normal. This case exemplifies the challenges in the diagnosis of coinfection of multiple respiratory pathogens and its associated complications. Greater awareness among clinicians would ensure an earlier and more accurate diagnosis of coinfection of EBV/CMV with other respiratory pathogen(s).