Background Central nervous system (CNS) malformations, including neural tube defects (NTDs), are the second most common type of birth defects worldwide and are major causes of childhood disability and mortality. We report the first analysis of birth prevalence in Western Honduras of CNS malformations including NTDs over 6 consecutive years. Methods Data from all patients with congenital CNS malformations and total live births for the period 2010–2015 were obtained through institution and regional registries from all 3 public referral hospitals in Western Honduras, representing 67 municipalities. Cases were identified using the International Classification of Diseases, Tenth Revision CNS malformation codes. Birth prevalence was calculated as cases per 10,000 live births. Results From 123,903 live births, 275 cases of CNS malformations were identified (54% females, 58% NTDs). Six-year birth prevalence of CNS malformations was 13.9–31.1. Spina bifida variants and anencephaly represented 80% and 19% of reported NTDs, respectively. Total 6-year prevalence of NTDs in Western Honduras was 7.0–17.4 over years studied. In 6 municipalities, average prevalence was >30 (maximum 49.0). Conclusion This is the first study reporting disease burden of CNS malformations in Western Honduras. The nationwide birth prevalence of NTDs in rural Honduras may have decreased since the implementation of prenatal health policies in 2005. However, we identified regions with unexpectedly elevated prevalence, indicating high regional prevalence that could be targeted for improved preventive efforts, ultimately decreasing the burden of these conditions.