It has been hypothesized that the ingestion of aspirin by women during pregnancy increases their infants' risk of certain congenital heart defects. Using data from a large program of case-control surveillance of congenital malformations, we evaluated this hypothesis. The case groups were made up of infants with any structural cardiac defect (n = 1381) and five selected cardiac defects (the subgroups were not mutually exclusive): aortic stenosis (n = 43), coarctation of the aorta (n = 123), hypoplastic left ventricle (n = 98), transposition of the great arteries (n = 210), and conotruncal defects (n = 791). First-trimester aspirin use among the mothers of these infants was compared with that among the mothers of a control group of infants with other malformations (n = 6966). The prevalence of any maternal aspirin use was similar for cases (25 to 33 percent) and controls (27 percent). The relative risks (and 95 percent confidence interval) among infants whose mothers were aspirin users as compared with those whose mothers did not use aspirin, adjusted for potential confounding factors, were 0.9 (0.8 to 1.1) for any cardiac defect, 1.2 (0.6 to 2.3) for aortic stenosis, 1.0 (0.6 to 1.4) for coarctation, 0.9 (0.6 to 1.4) for hypoplastic left ventricle, 0.9 (0.6 to 1.2) for transposition of the great arteries, and 1.0 (0.8 to 1.2) for conotruncal defects. Furthermore, no dose-effect pattern was identified. The findings of this study indicate that aspirin use during the first trimester of pregnancy does not increase the risk of congenital heart defects in relation to that of other structural malformations.