Human cytomegalovirus (HCMV) remains one of the major pathogens in immunocompromised patients (AIDS and transplants) and the main cause for congenital infections leading from slight cognitive defects up to severe mental retardation. The drugs that are currently available for the treatment of HCMV infections, i.e. ganciclovir, foscarnet and cidofovir, are all acting at the level of the viral DNA polymerase. Here we describe an entirely new molecule, the 2-chloro-3-pyridin-3-yl-5,6,7,8-tetrahydroindolizine-1-carboxamide (CMV423), that shows very potent in vitro activity against HCMV. CMV423 is highly active against HCMV reference strains and clinical isolates, but also against those strains, isolated from patients or emerging after in vitro selection, that are resistant to either ganciclovir, foscarnet or cidofovir. CMV423 also showed activity in two ex vivo models, that are both highly relevant for the pathophysiology of HCMV, the retinal pigment epithelial and the bone marrow stromal cell assays. Viral antigen expression analysis by flow cytometry, as well as time of addition experiments, confirmed that CMV423 acts on a step of the viral replicative cycle that precedes the DNA polymerase step and, most likely, coincides with the immediate early (IE) antigen synthesis. Finally, CMV423 combined with either ganciclovir, foscarnet or cidofovir in checkerboard experiments demonstrated a highly synergistic activity.