Background/Objectives <p>Human cytomegalovirus (HCMV) infection was scarcely reported as a prejudicing factor of CLP incidence. The aim of this study is to report an association between HCMV infection and incidence of severe orofacial clefts.</p> Materials/Methods <p>Five infants with severe orofacial clefts were included in the current study. One of the infants is with an oblique facial cleft extended to the left orbit and associated with missing left eyeball. Another infant was with facial cleft extending downward resulting in a clefted lower lip, clefted mandible and clefted tongue. All the patients’ mothers were evaluated for the amount of HCMV IgG in blood samples.</p> Results <p>All the five mothers of the included infants had a positive HCMV IgG results in the collected blood samples with the value of 908.8 (± 400.6). The amount of HCMV IgG was higher in cases with more severe clinical presentation.</p> Limitations <p>Due to the rarity of cases with severe orofacial clefts, only 5 patients were included. Lake of genetic data and control group are another limitations.</p> Conclusion <p>Within the limitation of the rareness of cases with severe orofacial clefts, HCMV infection to mothers before or during pregnancy might be a predisposing factor of incidence of severe orofacial clefts.</p>