In recent years, an increase in the rate of gastroschisis has been documented in several countries throughout the world. Based on accumulating evidence that a maternal immunologic response to a novel set of paternal antigens may be involved in risk for several adverse pregnancy outcomes, including preeclampsia, reduced birth weight, and preterm delivery, we tested the hypothesis that a pregnancy following a change in fathers (change in paternity) may be a risk factor for gastroschisis. Using a case-control design, we compared the prevalence of change in paternity with the index pregnancy in 102 mothers of isolated gastroschisis cases to the prevalence of change in paternity in 117 mothers of non-malformed infants and 78 mothers of infants with neural tube defects or oral clefts. In a multivariate analysis, the adjusted odds of change in paternity in multigravid case mothers were 7.81 times higher (95% Confidence interval 2.80-21.88) relative to multigravid mothers of malformed and non-malformed controls combined, after adjustment for maternal age. These data suggest that maternal immune factors may play a role in the cause of gastroschisis. Further research is needed to corroborate these findings and to elucidate possible immunologic mechanisms involved in the pathogenesis of gastroschisis.