Cortical projections arising from areas 4 and 6 and terminating in midbrain cell groups known to project to the inferior olive (IO) have been studied in the cat. Injections of the bidirectional tracers horseradish peroxidase (HRP) and wheat germ agglutinin (WGA) conjugated to HRP were made into the midbrain. All cases of lateralized midbrain injections resulted in virtually ipsilateral labelling of lamina V cortical neurons. Retrogradely labelled neurons in cortical areas 4 and 6 were found after injections located in the interstitial nucleus of Cajal (INC), nucleus of Darkschewitsch (ND), and in the caudal parafascicular (Pf) and subparafascicular (sPf) nuclei (perifascicular region, PF). Injections that were more caudal and within the parvi- and magnocellular red nucleus (RNp and RNm) labelled cells not only in areas 4 and 6 but also in portions of adjacent areas 3a, 3b, 5a, and 7. These midbrain injections also resulted in the anterograde labelling of projections observed to terminate in the ipsilateral IO. The distribution in the midbrain of projections arising from cortical areas 4 and 6, and portions of areas 3a and 3b, was studied with autoradiographic methods. After injections of tritium-labelled amino acids in those cortical areas, a pattern of largely ipsilateral terminations was revealed. Whereas all cortical areas studied labelled the PF, differential grain distributions in central mesencephalic nuclei were apparent after injections in various portions of the motor and adjacent somatosensory cortex. Injections involving the frontal eye fields (FEF) labelled the INC bilaterally, but ipsilateral terminations were densest. These cases also labelled the region of the fields of Forel. When the neck region of the cortex was involved in the injections, the more caudal aspects of the INC (INCc) and the RN were labelled. The cortical areas related to the upper limb gave rise to terminations in the ND and the RNp. Contributions to both ND and RNp inputs from injections in the FEF and neck regions were also occasionally but not consistently noted. A relatively discrete injection in the vibrissae field weakly labelled ND. Additional components of the motor cortical projections to the superior colliculus (SC) and pretectal nuclei were also analysed since those regions also project to the IO. Cortical regions involving the representation of the neck musculature were shown to project principally ipsilaterally to lamina IV of the SC as well as to the anterior pretectal nucleus.(ABSTRACT TRUNCATED AT 400 WORDS)