Several investigators have reported Hispanics to be at elevated risk for neural tube defects (anencephaly and spina bifida). Factors contributing to this risk have not been established. The authors conducted a case-control study of neural tube defects (NTDs) among births occurring in Harris County, Texas, from April 1, 1989, through December 31, 1991. Through the use of multiple ascertainment methods, 59 cases of anencephaly and 32 cases of spina bifida were detected. Controls (n = 451) were sampled for the same time period from Harris County vital records. Regardless of how Hispanic ethnicity was classified, having a Hispanic parent was a risk factor for both anencephaly and spina bifida. The primary etiologic question was whether increased NTD risk in Hispanics is explained by maternal diabetes or by other factors (e.g., maternal birthplace, prenatal care, reproductive history, age, socioeconomic status). Mexico-bom Hispanics were no more likely than Texas-bom Hispanics to deliver a fetus or infant with an NTD. Having a Hispanic mother was a risk factor for anencephaly among infants bom to women with early prenatal care (odds ratio (OR) = 4.54 95% confidence interval (Cl) 2.21–9.40) but not for those bom to latecomers. Earlier prenatal care seemed “protective” for non-Hispanics (OR = 0.18, 95% Cl 0.06–0.65) but not for Hispanics. After simultaneous adjustment for eight variables in multivariate analysis, having a Hispanic (versus non-Hispanic) mother remained a strong risk factor for both anencephaly (OR = 2.58,95% Cl 1.19–5.61) and spina bifida (OR = 3.71, 95% Cl 1.48–9.31). Any previous pregnancy termination/fetal loss was also associated with anencephaly in a final logistic regression model (OR = 2.48, 95% Cl 1.20–5.10), and having a teenage mother (aged Am J Epidemiol 1996;143:12–24