BACKGROUND: Disturbances in the central nervous system originating during foetal life may increase the risk of schizophrenia. AIMS: To illuminate the hypothesis that prenatal exposure to analgesics may affect foetal neurodevelopment, leading to increased risk of schizophrenia in adulthood. METHOD: Using data from the Copenhagen Perinatal Cohort and from the Danish Psychiatric Central Register, we studied the relationship between prenatal exposure to analgesics and the risk of schizophrenia. The effect of prenatal exposure was adjusted for parental history of schizophrenia, second-trimester viral infections, concomitant drug treatment during pregnancy, an index of pregnancy complications, parental social status and parental age. RESULTS: In a risk set of 7999 individuals, 116 cases of schizophrenia were found (1.5%). Prenatal exposure to analgesics in the second trimester was associated with an elevated risk (adjusted odds ratio 4.75, 95% CI1.9-12.0). Independent of the covariates, the effect remained statistically significant. CONCLUSIONS: Independent of a wide range of possible confounders, a significant association between second-trimester exposure to analgesics and increased risk of schizophrenia was observed.