There is an ongoing discussion regarding conflicting data on malformation rate in children born after intracytoplasmic sperm injection (ICSI). A prospective, multicentric, control cohort study was done in Germany. Fifty-nine centres prospectively recruited pregnancies before the 16th week of gestation, which were included in the study if they were ongoing beyond this time. Children were examined according to a standardized procedure. A control cohort of children conceived spontaneously was taken from a prospective birth registry (Mainzer Modell), where children were examined accordingo the exact same criteria as the ICSI cohort. Major malformation rate was calculated, based on data of all liveborn and stillborn children, as well as on all spontaneous and induced abortions, beginning with the 16th week of gestation. In the ICSI cohort, 8.6% of infants (291/3372), and in the control cohort 6.9% of infants (2140/30940), had a major malformation. This resulted in a crude relative risk (RR) of 1.25 (95% confidence interval 1.11-1.40). There was no influence ofsperm origin on major malformation rate in children born after ICSI. There is an increased risk for a child born after ICSI to have a major malformation compared with a child that has been spontaneously conceived. Based on knowledge of the early developmental steps following ICSI, as well as on data of conventional IVF in general, it is assumed that this increased risk is due to parental factors causing the infertility, which has led to ICSI in the first place.