Compelling evidence suggests that there is a considerable overlap in structural and functional alternation in the brain between different neuropsychiatric disorders. However, whether these overlaps are specific for schizophrenia has yet to be investigated. A total of 36 patients with paranoid schizophrenia, 43 patients with major depressive disorder (MDD), and 44 healthy controls were recruited to undergo resting-state functional magnetic resonance imaging (rs-fMRI) for analysis of regional homogeneity (ReHo). Twelve regions of interest (ROIs) in the frontal and temporal lobes were generated and one-way ANOVA was performed to test the ReHo differences within these ROIs between the above three groups. The ReHo values within ROIs were extracted to investigate whether a left-right asymmetry existed in a mental disorder. One-way ANOVA showed significant differences in ReHo in the right superior frontal gyrus and left superior temporal gyrus; post hoc analysis revealed that schizophrenic patients had lower ReHo in the left superior temporal gyrus than either control subjects or patients with MDD. Increased ReHo was observed in the right superior frontal gyrus in schizophrenic patients compared with control subjects, and a left-less-than-right asymmetry was also found in this region in schizophrenic patients. The above alterations in ReHo were not affected by age and genders. Our study suggests that the altered ReHo in the superior frontal and temporal gyrus may be specific for schizophrenia rather than MDD. A left-less-than-right asymmetry activation pattern may exist in the resting-state superior frontal gyrus in schizophrenia. This finding would be helpful for better understanding the pathological mechanisms of schizophrenia. © 2012 Wiley Periodicals, Inc.