A quantitative electron microscope analysis was performed to determine the effects of 1-year administration of either haloperidol or clozapine on the ultrastructure of synapses in layer VI of rat medial prefrontal cortex. The average caliber of dendritic shafts was significantly decreased in the haloperidol-treated group, but not in clozapine-treated animals; however, there was no difference between the means of the two drug-treated groups. Both drug-treated groups showed a significant decrease in the relative distribution of axodendritic synapses displaying asymmetric postsynaptic membrane specializations, while there was an increase in synapses with either a symmetric membrane specialization or no specialization at all. Axospinous synapses of the clozapine-treated group showed a shift in the relative distribution of synaptic subtypes paralleling that found for axodendritic synapses. There was no change in the number of axon terminals forming a synapse on dendritic cross-sectional profiles in the neuroleptic-treated groups. Similarly, no change in the average size of axon terminals or synaptic vesicle density was detected. These data suggest that both typical and atypical neuroleptics, when administered over an extended period of time, may induce relative shifts in the distribution of excitatory and inhibitory elements synapsing on dendritic shafts and, to a lesser degree, spines. Such alterations in synaptic relationships may provide insight into the interaction of neuroleptics with intrinsic components in layer VI of medial prefrontal cortex.