Antipsychotic drugs act on the dopaminergic system (first-generation antipsychotics, FGA), but some also directly affect serotonergic function (second-generation antipsychotics, SGA) in the brain. Short and long-term effects of these drugs on brain physiology remain poorly understood. Moreover, it remains unclear whether any physiological effect in the brain may be different for FGAs and SGAs. Immediate (+3.30 h) and different effects of single-dose FGA (haloperidol, 3 mg) and a SGA (aripiprazole, 10 mg) on resting cerebral blood flow (rCBF) were explored in the same 20 healthy volunteers using a pulsed continuous arterial spin labeling (pCASL) sequence (1.5T) in a placebo-controlled, repeated measures design. Both antipsychotics increased striatal rCBF but the effect was greater after haloperidol. Both decreased frontal rCBF, and opposite effects of the drugs were observed in the temporal cortex (haloperidol decreased, aripiprazole increased rCBF) and in the posterior cingulate (haloperidol increased, aripiprazole decreased rCBF). Further increases were evident in the insula, hippocampus, and anterior cingulate after both antipsychotics, in the motor cortex following haloperidol and in the occipital lobe the claustrum and the cerebellum after aripiprazole. Further decreases were observed in the parietal and occipital cortices after aripiprazole. This study suggests that early and different rCBF changes are evident following a single-dose of FGA and SGA. The effects occur in healthy volunteers, thus may be independent from any underlying pathology, and in the same regions identified as structurally and functionally altered in schizophrenia, suggesting a possible relationship between antipsychotic-induced rCBF changes and brain alterations in schizophrenia. Hum Brain Mapp, 2013. © 2012 Wiley Periodicals, Inc.