Objective: To tabulate individual allele frequencies and total carrier frequency for Smith-Lemli-Opitz syndrome (SLOS) and compare expected versus observed birth incidences. Design: Retrospective analysis of patients from the general population who have undergone carrier screening for SLOS. Setting: Individuals were offered and elected carrier screening in their respective physician's offices. Patients: 262,399 individuals with no indication of family or personal history of Smith-Lemli-Opitz syndrome, primarily US-based, screened for Smith-Lemli-Opitz syndrome mutations as part of an expanded carrier screening panel. Intervention(s): Data on mutations in the DHCR7 gene causing SLOS were analyzed to estimate carrier frequencies in multiple ethnic groups. SLOS birth incidences obtained from existing literature are then compared to our data to estimate the effect of SLOS on fetal survival. Main Outcome Measure(s): Individual and cumulative allele frequencies stratified by self-reported patient ethnicity. Results: SLOS carrier frequency is highest in individuals of Ashkenazi Jewish ancestry (1 in 43) and Northern Europeans (1 in 54). Comparing predicted birth incidence to that observed in published literature suggests that approximately 42% to 88% of affected conceptuses experience fetal demise. Conclusion: SLOS is relatively frequent in certain populations and, due to its impact on fetal survival, merits preconception screening.