Cytomegalovirus (CMV) is a virus that infects both normal and compromised hosts. In normal hosts, CMV presents most often as an "infectious mononucleosis-like" illness, but less commonly may present as community-acquired pneumonia (CAP), colitis, hepatitis, or fever of unknown origin. In compromised hosts, CMV often presents as CAP, encephalitis, retinitis, adrenalitis, hepatitis, or colitis. Not unlike parvovirus B19, CMV is an immunomodulatory virus that may cause or exacerbate rheumatic/inflammatory disorders, particularly systemic lupus erythematosus (SLE). Acute CMV infection may result in de novo SLE or more commonly may precipitate an SLE flare. In patients with SLE who are taking immunosuppressives, CMV increases the degree of immunosuppression of cell-mediated immunity. We present the case of a 40-year-old woman with SLE who presented with severe CMV CAP. CMV infection was suspected because of 2 nonspecific laboratory findings: increased serum transaminases and atypical lymphocytes in the peripheral smear. SLE is a multisystem autoimmune disorder that spares the liver. Therefore, in a patient with SLE who experiences an SLE flare, increased serum transaminases should suggest the possibility of CMV. In patients with SLE with flare, the likelihood of CMV is further increased if serum transaminases are elevated with atypical lymphocytes and should prompt specific testing for CMV. This patient's severe CMV CAP was treated successfully with oral valganciclovir, and she made a slow but complete recovery.