The present study was conducted to examine the spatial organization of locus coeruleus (LC) neurons that project to rat cerebral cortex. Long-Evans hooded rats received unilateral pressure injections of horseradish peroxidase (HRP) in either frontal (n = 6) or sensorimotor (n = 11) or occipital (n = 7) cortex to determine the intranuclear location of LC neurons which project to specific neocortical regions. Coronal and sagittal sections (40-100 micron) through the LC were examined by light microscopy after carrying out the tetramethyl benzidine reaction and staining with neutral red. The locations of retrogradely labeled cells were recorded on a three-dimensional biological coordinate system maintained by a computer linked to the light microscope. LC neurons labeled from cerebrocortical injections of HRP were primarily located in the ipsilateral and to a lesser extent (fewer than 5% of total labeled cells) in the contralateral nucleus. Coeruleocortical projection neurons were concentrated in the caudal three-fifths of the dorsal division of the ipsilateral LC. Within this portion of the nucleus, HRP-filled neurons were distributed so that individual groups of cells projecting to occipital or sensorimotor or frontal cortex were coarsely aligned in a dorsal to ventral array, respectively. Moreover, in the sagittal plane of the nucleus the pattern of labeling was spatially graded so that the subset of neurons projecting to the occipital cortex was displaced more caudally in the LC than the groups of cells sending axons to sensorimotor or frontal cortex. Only the frontal area of the cortex received a projection from both dorsal and ventral divisions of the ipsilateral LC. Computer-assisted analysis of the data further suggested that neocortical projection neurons in the dorsal LC are loosely organized into two groups which run rostrocaudally through the core of the caudal nucleus. The zone of labeling resulting from injections confined to the neocortical gray matter overlapped with but was not coextensive with that observed following injections into the caudate, hippocampus, and cerebellum. These results suggest that partially overlapping subsets of LC cells might independently influence separate populations of neurons within noradrenergic terminal fields of the neocortex.