Background The clinical triad of fever, pharyngitis, and lymphadenopathy was first described in 1889 as “glandular fever” and later defined as infectious mononucleosis. We present a case report and review of mononucleosis-like syndromes in an immunocompetent patient. The review of common etiologies includes Epstein-Barr virus (EBV), acute human immunodeficiency virus (HIV), human herpesvirus 6 (HHV-6), cytomegalovirus (CMV), and Toxoplasmosis gondii. Case Vignette A 37-year- old, immunocompetent female presented with a three-week history of fever, pharyngitis, fatigue, night sweats, and abdominal pain. Physical examination revealed hepatosplenomegaly, but no lymphadenopathy, rashes, or tender joints. Investigations showed lymphocytosis and a normal peripheral smear. A Hematology consultation excluded hematologic malignancy. Her CD4/CD8 ratio was 0.2 in keeping with a viral infection, but EBV monospot test was negative. Serology for hepatitis B and C were negative. Human immunodeficiency virus (HIV) testing was not done in the absence of risk factors. Quantitative PCR for CMV was positive with a value of 965.25 units/mL. The patient was diagnosed with CMV viremia and treated with a two-week course of valganciclovir with resolution of symptoms. A two-month follow-up revealed a normal complete blood count and resolving hepatosplenomegaly. Conclusions In immunocompetent patients presenting with symptoms of mononucleosis, the differential diagnosis should include EBV, CMV, HHV-6, acute HIV and Toxoplasmosis gondii. CMV commonly affects young patients and is less associated with tonsillitis, pharyngitis, and lymphadenopathy. HHV-6 can present with headaches, encephalitis, and abdominal pain. Consideration of acute HIV mononucleosis should prompt early serologic testing. Toxoplasmosis is often associated with undercooked food or cat excrement, requiring anti-IgM antibody testing to distinguish from EBV. Although EBV infectious mononucleosis may be suspected, the general practitioner should consider a complete review of other infectious etiologies.