In a case-control surveillance program, first trimester medication use was studied in relation to gastroschisis. There were 76 cases of gastroschisis which were compared with 2,142 controls with other major malformations. For pseudoephedrine use, we found a significantly elevated relative risk of 3.2 (95% confidence interval, 1.3-7.7), with adjustment for confounding. Multivariate relative risks for analgesic/antipyretics and another decongestant were as follows: salicylates, 1.6 (0.9-2.7); acetaminophen, 1.7 (1.0-2.9); ibuprofen, 1.3 (0.4-3.7); and phenylpropanolamine, 1.5 (0.4-5.4). No increases in risk were identified for use of antihistamines, antibiotics, oral contraceptives, or spermicides. Because salicylates, pseudoephedrine, and phenylpropanolamine are vasoactive, the elevated risks for these drugs support the hypothesis of vascular disruption in the etiology of gastroschisis. We therefore examined maternal use of vasoactive medications in relation to a second case group of 416 infants with hetereogeneous defects suspected to have a vascular etiology. Relative risks for salicylates, ibuprofen, pseudoephedrine, phenylpropanolamine, and other decongestants approximated unity. These positive associations must be considered tentative. They have not been reported previously and should be confirmed independently. Also, acetaminophen, which may be taken for the same indications as salicylates and decongestants, but is not thought to be vasoactive, was associated with gastroschisis, suggesting that identified associations may be due to an underlying maternal illness.