Background: Natural cell death due to apoptotic mechanisms has been described in various species. Relatively few studies examined this process in humans. Aim: To investigate the distribution of apoptosis in fetal brain tissue. Design: We examined apoptosis in the frontal region of human fetal brain by the TUNEL method in nine fetuses with no neurological conditions, gestational age 14-26 weeks, and three fetuses with structural anomalies of the nervous system (lumbar meningomyeloceles, n=2, hydrocephalus, n=1). Results: In normal fetuses, TUNEL-positive cells were most concentrated in the intermediate zone (IZ) and between 18 and 22 weeks of gestation; cortical apoptosis was not prominent. The fetus with hydrocephalus had increased numbers of TUNEL-positive cells while those with neural tube defects did not differ from normals. Conclusion: The definition of normally occurring apoptosis may provide a basis for further studies directed at central nervous system (CNS) malformations. © 2003 Elsevier Science Ireland Ltd. All rights reserved.