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 anencepahly 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-born Hispanics were no more likely than Texas-born Hispanics to deliver a fetus or infant with an NTD. Having a Hispanic mother was a risk factor for anencephaly among infants born to women with early prenatal care (odds ratio (OR) = 4.54, 95% confidence interval (CI) 2.21-9.40) but not for those born to latecomers. Earlier prenatal care seemed "protective" for non-Hispanics (OR = 0.18, 95% CI 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% CI 1.19-5.61) and spina bifida (OR = 3.71, 95% CI 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% CI 1.20-5.10), and having a teenage mother (aged < 20 years) approached significance (OR = 2.21, 95% CI 0.92-5.31). "Hispanic mother" was the only study variable significantly associated with spina bifida in multivariate analysis. Results for diabetes suggested no association with anencephaly (OR = 1.24, 95% CI 0.25-6.17). An increased risk of NTDs among Hispanics remained after controlling for other factors. For anencephaly, this risk might be partially explained by economic and cultural differences between Hispanics and non-Hispanics, and the effect of these factors on rates of prenatal diagnosis and elective pregnancy termination.