During brain development, the majority of neurons undergo programmed cell death. It is now clear that caspases are involved in this process of selective induction of neuronal apoptosis, yet the signals for this caspase activation remain undefined. As an upstream activator of these enzymes, the death receptor CD95 (Fas, APO1) was recently shown on neurons in the cornu ammonis (CA)2 and CA3 hippocampal subfields of early postnatal mice and rats. In vitro, cortical neuroblast cells are susceptible to CD95 ligand (CD95L, FasL, APO-1 L)-induced apoptosis. It was therefore suggested that the CD95/CD95L system is involved in neuronal apoptosis during hippocampal development. We therefore performed a blinded study comparing field size and neuronal density in the hippocampi of p20 CD95-deficient (lpr), CD95L-deficient (gld) and C57 mice. Whereas field sizes did not differ significantly between these strains, paired Mann-Whitney analyses revealed an increased number of neurons in the CA2 regions of CD95-deficient mice (P = 0.008), and minor, yet at 1% nonsignificant, differences between gld, lpr and C57 strains in the CA1 and CA3 regions. However, joint comparison of the three strains using the Kruskal-Wallis test rendered all differences insignificant. We conclude that the CD95/CD95L system is either not involved, or can be replaced by alternate mechanisms in the control of neuronal populations during hippocampal development.