The impact of intracerebroventricular administration of 6-hydroxydopamine (6-HDA) on the dopamine (DA)-containing nigrostriatal projection was determined by regional histochemical and biochemical analyses. One week postinjection, we observed that tyrosine hydroxylase (TH)-positive terminals were almost completely absent from the medial portion of striatum but gradually increased in density toward the lateral margin of this structure. A similar gradient was indicated by fluorescence histochemistry and biochemical analyses of DA. In contrast, the 6-HDA-induced changes in TH activity and in dihydroxyphenylacetic acid content were less severe and showed little or no medial-to-lateral gradient. These high levels of TH activity and DOPAC content, relative to local DA concentrations, suggest an increase in the synthesis and release of DA from residual terminals that may serve to compensate for the brain damage. By 4 months postlesion, both histochemical and biochemical analyses indicated the presence of more DA terminals in striatum than there had been one week postlesion. This change was most markedly obvious in the medial striatum, which had been almost completely devoid of terminals at one week postlesion. Retrograde tracing experiments revealed that terminals appearing in the medial striatum at 4 months postlesion arise from the same region of the substantia nigra that innervates the medial striatum in the intact animal. Thus, no change in the topographic relation between substantia nigra and striatum occurred as a result of the lesion.