As a result of numerous conflicting reports, we designed a prospective controlled study to determine the inherent risk of aneuploidy with second-trimester fetal choroid plexus cysts. Our controls were patients who had ultrasonography and genetic amniocentesis, between 15 weeks and 22 weeks, menstrual age, by the same sonologist on the same day as a study subject with a choroid plexus cyst. Sixty-three cases of fetal choroid plexus cysts were detected in 3247 second-trimester examinations (1.9%). Six chromosomally abnormal fetuses [Trisomy 18 (3), Down syndrome (2), Klinefelter syndrome] were found in the cyst group (9.5%) with only one Trisomy 21 among the controls (0.5%) (p < .002). Of note, 5 of 21 (23.8%) fetuses with cysts greater than 5 mm in diameter had aneuploidy, as compared with only 1 of 42 (2.4%) chromosomal anomalies with smaller cysts (p < .02). We conclude that fetal choroid plexus cysts are an independent risk factor for chromosomal anomalies; genetic counseling and prenatal chromosomal analysis are indicated.