Blood-oxygenation-level-dependent (BOLD) brain changes underlying response to quetiapine were examined using passive viewing of emotionally negative stimuli. Twelve DSM-IV schizophrenia patients with blunted affect (BA+) were scanned before and after 22 weeks of quetiapine treatment. Whole-brain, voxel-based methods were used to assess the differential hemodynamic response to quetiapine. In addition, a post hoc comparison to an independent group of 11 schizophrenia patients without blunted affect (BA-) was performed to compare them with BA+ (postquetiapine) in response to emotion processing. A 22-week treatment with quetiapine resulted in significant clinical improvement in the 12 study completers (mean +/- SD posttreatment PANSS blunted affect score of 5.50 +/- 0.76 at baseline to 2.08 +/- 1.00 at end point; t = 7.78, df = 11, P < 0.0001). Treatment response was associated with significant BOLD changes: increases in prefrontal cortex activation particularly in the right dorsolateral prefrontal cortex (DLPFC, BA 46) and the right anterior cingulate cortex (ACC, BA 32); and in the left putamen, right anterior temporal pole (ATP), and right amygdala. Conversely, before treatment with quetiapine, the same subjects activated the midbrain bilaterally and the right pons. The post hoc conjunctional analyses demonstrated that BA- subjects activated the left ACC, left insula, left ATP (BA 21), left ATP (BA 38), left amygdala, and right medial prefrontal cortex. Quetiapine seems to affect clinical recovery by modulating the functioning of specific brain regions. Unique BOLD changes in the putamen and DLPFC with quetiapine, in the BA+ postquetiapine, may reflect modality-specific effects. Controlled studies are needed to further assess these preliminary findings.