Objectives The aim of this study was to investigate whether there is an association between enlarged nuchal translucency (NT) and orofacial clefts. Methods The pregnancy outcome of women who underwent an NT measurement between January 2000 and November 2008 was reviewed. All orofacial clefts detected prenatally and postnatally in karyotypically normal fetuses/infants were reviewed and a distinction was made between isolated defects and clefts as part of multiple congenital anomalies (associated). Results The cohort included 8638 fetuses. The NT was enlarged in 746 (8.6%). The karyotype was normal in 8347 fetuses, including 513 of the fetuses with an enlarged NT. Isolated or associated cleft lip, with or without cleft palate (CL/P), or cleft palate (CP) were diagnosed in 18 chromosomally normal fetuses (an incidence of 2.2 per 1000). In eight of these cases the NT was normal (8/7834; an incidence of 1.0 per 1000) and in the remaining 10 it was enlarged (10/513; an incidence of 19.5 per 1000). CL/P and CP were isolated or associated in three and seven of the chromosomally normal fetuses with an enlarged NT, respectively. Euploid fetuses with an enlarged NT had a relative risk for any clefts of 19 and a relative risk for isolated or associated clefts of8 and 53, respectively (P < 0.001). Conclusions Chromosomally normal fetuses with an enlarged NT have an increased risk of orofacial clefts. CL/P and CP are, in these fetuses, mostly associated findings, frequently part of a genetic syndrome. A detailed ultrasound examination with special attention given to the orofacial area is indicated in these fetuses. Copyright © 2010 ISUOG.