Antipsychotic drugs are the primary therapeutic treatment for schizophrenia. In addition to their dopaminergic/serotonergic function, atypical antipsychotics differ from conventional antipsychotics in the way they affect glutamatergic receptor function. A cellular correlate of this may be the modulation of dendritic spines (DS). Here, we demonstrate that in rat dissociated hippocampal neurons 1.0 μM clozapine administration increased DS-enriched protein spinophilin by 70%, increased post-synaptic protein shank1a puncta density by 26% and increased overall primary dendrite DS density by 59%. Filopodia and mushroom DS were particularly affected by clozapine. Conversely, 0.1 μM haloperidol decreased spinophilin protein by 40%, caused a 25% decrease in shank1a puncta and reduced the numbers of filopodia. In contrast, neither haloperidol nor clozapine induced any change in the levels of the pre-synaptic protein synapsin. This indicates that clozapine and haloperidol differentially regulate DS and post-synaptic plasticity. These findings may provide a molecular and cellular correlate to the superior therapeutic profile of clozapine when compared with haloperidol.