To evaluate the sensitivity and specificity of ultrasound for detecting prenatal facial clefts in low-risk and high-risk populations. This study prospectively followed up a non-selected population, namely all pregnant women who underwent routine second-trimester prenatal ultrasound screening in the Utrecht region during the 2-year period from January 2007 to December 2008. A total of 35 924 low-risk and 2836 high-risk pregnant women underwent ultrasound screening. Orofacial clefts were present in 62 cases, an incidence of 1:624. The distribution of clefts was as follows: 18 (29%) cleft lip, 25 (40%) cleft lip with cleft palate, 17 (27%) cleft palate only, one median cleft and one atypical cleft. Of these, 38 (61%) were unilateral and 23 (37%) were bilateral. Thirty-nine per cent (24/62) had associated anomalies, with most chromosomal defects found in the cleft lip with cleft palate and cleft palate only groups. Cleft lip with or without cleft palate was detected prenatally in 38/43 cases, a sensitivity of 88%. No case of cleft palate only was detected prenatally. There were three false-positive cases, of which two were fetuses with multiple congenital deformities. Ultrasound screening has a high sensitivity for the detection of cleft lip with and without cleft palate in high-risk and low-risk pregnancies in our region, where well-trained sonographers carry out primary screening. The key to a high sensitivity of prenatal ultrasound is likely to be a combination of excellent training of sonographers, referral to specialized centers when a cleft is suspected, routine visualization of the fetal face and advances in ultrasound techniques.