Gastroschisis and small intestinal atresia (SIA) are birth defects that are thought to arise from vascular disruption of fetal mesenteric vessels. Previous studies of gastroschisis have suggested that risk is increased for maternal use of vasoactive over-the-counter medications, including specific analgesics and decongestants. This retrospective study evaluated the relation between maternal use of cough/cold/analgesic medications and risks of gastroschisis and SIA. From 1995 to 1999, the mothers of 206 gastroschisis cases, 126 SIA cases, and 798 controls in the United States and Canada were interviewed about medication use and illnesses. Risks of gastroschisis were elevated for use of aspirin (odds ratio = 2.7, 95% confidence interval: 1.2, 5.9), pseudoephedrine (odds ratio = 1.8, 95% confidence interval: 1.0, 3.2), acetaminophen (odds ratio = 1.5, 95% confidence interval: 1.1, 2.2), and pseudoephedrine combined with acetaminophen (odds ratio = 4.2, 95% confidence interval: 1.9, 9.2). Risks of SIA were increased for any use of pseudoephedrine (odds ratio = 2.0, 95% confidence interval: 1.0, 4.0) and for use of pseudoephedrine in combination with acetaminophen (odds ratio = 3.0, 95% confidence interval: 1.1, 8.0). Reported fever, upper respiratory infection, and allergy were not associated with risks of either defect. These findings add more evidence that aspirin use in early pregnancy increases risk of gastroschisis. Although pseudoephedrine has previously been shown to increase gastroschisis risk, findings of this study raise questions about interactions between medications and possible confounding by underlying illness.