The main concern of this chapter is to present cytomegalovirus infection in critically ill patients. Cytomegalovirus (CMV) is widely distributed around the globe. Infection is more common in less developed countries with poor hygienic conditions. In critically ill patients reactivation of the latent infection is mainly considered to be the cause of CMV disease, though acquisition of primary infection is also possible. CMV belongs to Betaherpesvirinae subfamily. It is a double-stranded DNA virus and undergoes replication inside the host cell nucleus to produce characteristic large intranuclear inclusion body that is surrounded by a halo, giving rise to an “owl’s eye” appearance. Positive viral cultures, antigenemia, and DNAemia by PCR from blood or another clinical specimen are three methods of CMV. Ganciclovir is the mainstay of treatment for CMV disease. It is a nucleoside analogue and acts by inhibition of DNA synthesis.