Results of clinical and epidemiologic studies have shown an increased risk for neural tube defects (NTD) in infants whose mothers were exposed to heat during pregnancy. However, the risk for NTD in infants whose mothers had influenza during pregnancy has not been well studied. This population-based case-control study of infants born in metropolitan Atlanta, Georgia, from 1968 through 1980 included 385 infants with NTD, 3,647 infants with other birth defects, and 2,676 infants without birth defects. Of the 385 mothers of case infants, 31 reported having a 2-day or longer episode of flu with fever from 1 month before through 3 months after conception (odds ratio (OR) = 3.0; 95% confidence interval (CI) 1.9-4.7). Infants of mothers who took medications for their episodes of flu with fever had an even higher risk for NTD (OR = 4.3, 95% CI 2.6-7.1). When mothers of infants with birth defects other than NTD were used as controls, an increased risk of NTD remained for flu with fever (OR = 1.7, 95% CI 1.1-2.5). There was no increased risk for NTD among the infants of mothers who reported fever from causes other than flu. Because of the heterogeneity of maternal flu, the individual contributions of infection, fever, and medications remain difficult to disentangle.