Inositol, a glucose isomer and second messenger precursor, regulates numerous cellular functions and has demonstrated efficacy in obsessive-compulsive disorder (OCD) through mechanisms that remain unclear. The effect of inositol treatment on brain function in OCD has not been studied to date. Fourteen OCD subjects underwent single photon emission computed tomography (SPECT) with Tc-99m HMPAO before and after 12 weeks of treatment with inositol. Whole brain voxel-wise SPM was used to assess differences in perfusion between responders and nonresponders before and after treatment as well as the effect of treatment for the group as a whole. There was 1) deactivation in OCD responders relative to nonresponders following treatment with inositol in the left superior temporal gyrus, middle frontal gyrus and precuneus, and the right paramedian post-central gyrus; 2) no significant regions of deactivation for the group as a whole posttreatment; and 3) a single cluster of higher perfusion in the left medial prefrontal region in responders compared to nonresponders at baseline. Significant reductions in the YBOCS and CGI-severity scores followed treatment. These data are only partly consistent with previous functional imaging work on OCD. They may support the idea that inositol effects a clinical response through alternate neuronal circuitry to the SSRIs and may complement animal work proposing an overlapping but distinct mechanism of action.