OBJECTIVE: The authors sought to determine whether prenatal exposure to infection and a positive family history of psychotic disorders interact synergistically to increase the risk of later developing schizophrenia. METHOD: The authors linked two national registers, the Medical Birth Register and the Finnish Population Register, to identify all women in Helsinki who received hospital treatment during pregnancy for an upper urinary tract infection (N=9,596) between 1947 and 1990. The Finnish Hospital Discharge Register was used to ascertain psychiatric outcomes in adulthood of offspring exposed to infection prenatally. Family history of psychotic disorders was determined by linking the Hospital Discharge Register and the Population Register. The authors used an additive statistical interaction model to calculate the amount of biological synergism between positive family history and prenatal exposure to infection. RESULTS: Prenatal exposure to infection did not significantly increase the risk of schizophrenia. However, the effect of prenatal exposure to pyelonephritis was five times greater in those who had a family history of psychosis compared to those who did not. The synergy analysis suggested that an estimated 38%-46% of the offspring who developed schizophrenia and had both prenatal exposure to infection and a positive family history of psychotic disorders did so as a result of the synergistic action of both risk factors. CONCLUSIONS: These findings support a mechanism of gene-environment interaction in the causation of schizophrenia.