Repeated episodes of cerebral hypoxia-ischemia can cause primarily striatal neuronal loss in the developing brain. We investigated the effect of repeated episodes of asphyxia on specific neuronal sub-populations of the basal ganglia in late-gestation fetal sheep. Asphyxia was induced in 10 fetal sheep (118-126 days gestation) by occluding the umbilical cord for 5 min. This procedure was repeated four times at 30 min intervals and the brains were fixed 3 days later for histopathology. Immunohistochemical markers were used to identify various populations of neurons in the striatum. Antibodies to calbindin were used to stain the GABAergic medium-sized striatal projection neurons and antibodies to somatostatin and parvalbumin to identify striatal interneurons. Striatal projection neurons to the globus pallidus were recognized by enkephalin immunoreactivity, while the striatonigral terminals were identified in the substantia nigra pars reticulata by substance P immunohistochemical labelling. The results showed a marked loss of calbindin staining in the striatum, evident by both reduced cell numbers and a decrease in neuropil staining. The number of parvalbumin immunoreactive cells was also reduced in the striatum, while somatostatin interneurons were selectively preserved. In addition, immunostaining for enkephalin in the globus pallidus and for substance P in the substantia nigra was markedly reduced. These results show that the stiatal GABAergic medium-sized projection neurons are severely affected by recurrent episodes of asphyxia. These findings are confirmed and extended by the results demonstrating that both the enkephalin/GABA striatopallidal and the substance P/GABA stiatonigral pathways are affected. The results of this study therefore suggest that the efferent striatal projections to the globus pallidus and to the substantia nigra may be involved in asphyxial episodes resulting in cerebral palsy.