Compared to first-generation antipsychotics (FGAs) such as haloperidol, second-generation antipsychotics (SGAs) such as olanzapine are found superior to improve cognitive performance and reduce negative symptoms with no extrapyramidal symptoms (EPS). These clinical effects of SGAs have been reported to be associated with the most replicated phenomenon, favorable changes in brain regional blood flow and volume. The changes in brain regional blood flow are shown to parallel changes in angiogenesis, which is primarily mediated by vascular endothelial growth factor (VEGF) through its receptor, Flk-1, on endothelial cells. Therefore, we studied the differential effects of time-dependent treatment (14 and 45 days) with haloperidol and olanzapine (2 and 10 mg/kg/day, respectively, in drinking water) on hippocampal levels of VEGF, its receptor Flk-1, and angiogenesis in adult rat. The levels of VEGF were determined by both Western blot analysis and ELISA, and Flk-1 levels were determined by Western blot analysis. Immunohistochemical analysis of rat endothelial cell antigen-1 (RECA-1) and laminin were used to evaluate the changes in angiogenesis. After 14 days of treatment with both haloperidol and olanzapine, the levels of VEGF and angiogenesis were significantly increased (p<0.001 vs vehicle for both), but 45 days of treatment with haloperidol reduced their levels back to levels in vehicle-treated rats. However, olanzapine treatment further increased VEGF levels (p<0.05 vs levels after 14 days of treatment). Changes in the levels of Flk-1 paralleled the changes in VEGF levels. Thus, the data indicate that haloperidol and olanzapine have distinct time-dependent patterns of regulation of VEGF and angiogenesis. These changes probably provide a new molecular mechanism to better explain their differential effects on the patterns of regional blood flow and associated changes in regional volume/neuroplasticity and psychopathology.