We have previously found typical neuroleptic exposure to be correlated with an increase in anterior cingulate volume over time in patients with schizophrenia. However, the effect of atypical neuroleptics on anterior cingulate volume and the clinical significance of these changes are not known. To determine if atypicals differ from typicals in their effect on anterior cingulate volume change over time and to assess the clinical significance of such changes, subjects with schizophrenia were compared to normal controls over time. Anterior cingulate volume was delineated with manual traces on magnetic resonance images of the brain in 31 neuroleptic-naïve subjects and 18 normal controls at admission and 2-3 years later. Neuroleptic exposure for each subject was calculated using a dose-year formula. Increased typical neuroleptics exposure over time was correlated to increased anterior cingulate volume over time (r = 0.92, p < 0.001), while increased atypical neuroleptics exposure was correlated to decreased anterior cingulate volume (r = -0.57, p < 0.006). Increased anterior cingulate volume was correlated to greater psychotic symptom improvement (r = 0.78, p < 0.010). Anterior cingulate volume changes over time are correlated differently with atypical versus typical neuroleptic exposure over time. The increase in anterior cingulate volume with typicals is correlated to improved psychotic symptoms over time.