The aim of this study was to evaluate whether the recovery observed after grafting of fetal nigral cells in 6-hydroxydopamine lesioned rats is due to the graft itself, and whether the participation of the remaining host dopaminergic system is necessary. The effects of unilateral 6-hydroxydopamine lesion on rotational behavior were not significantly affected by sham grafting or by sham grafting plus repeat ipsilateral lesion, but were suppressed by nigral grafting, and by contralateral lesion. Immunohistochemical and in situ hybridization study of right striata of rats subjected to right-side lesion then right-side sham-grafting, and of right and left striata from rats subjected to right-side lesion then right-side sham-grafting then repeat right-side lesion then left-side lesion, revealed (a) no significant amphetamine-induced Fos activation, (b) marked increases in preproenkephalin mRNA levels, and (c) decreases in preprotachykinin levels, with no significant differences in any of these variables among these three types of striata. After nigral grafting, however, intense Fos expression was observed in the striatum, and preproenkephalin and preproenkephalin mRNA levels returned to normal. This recovery was maintained after subsequent repeat ipsilateral 6-hydroxydopamine lesion followed by contralateral lesion. The results demonstrate that, after dopaminergic denervation, the nigral graft itself is able to induce recovery in the assessed parameters, and that these effects of grafting into striata with maximal unilateral 6-hydroxydopamine lesion are due to graft function, and are not significantly influenced by the remaining ipsilateral or contralateral host dopaminergic system. Additionally, it is interesting to note that bilateral denervation led to changes in striatal preproenkephalin and preproenkephalin mRNA levels similar to those observed after unilateral lesion.