A pertinent question in biological psychiatry is what differentiates responders and non-responders to pharmacological treatment. One possibility is that individual differences in the symptomatic spectrum as well as in the underlying biology of the disorder lead to the known 40% failure in pharmacological treatment. Our study aimed to maximize individual brain markers of obsessive-compulsive disorder (OCD) by applying single photon emission computed tomography (SPECT) during a provoked symptomatic state prior to and following treatment. Four brain SPECT scans were obtained from 26 OCD patients prior to and at 6 months of sertraline treatment. At each time point, two SPECT scans were performed in a counterbalanced order of two specific states; one a symptom-provoking condition and the other a relaxed condition. At 6 months of treatment, patients were divided into responders and non-responders according to a predetermined clinical criterion. Prospective responders showed significantly lower brain perfusion in the dorsal-caudal anterior cingulum and higher brain perfusion in the right caudate, when compared to non-responders, only during symptom provocation. When pre- and post-treatment scans during symptom provocation were compared, only responders showed significant change in brain response: increased perfusion in the left anterior temporal cortex and prefrontal cortex at 6 months' treatment. These findings suggest that obtaining functional brain imaging during specific symptom provocation emphasizes individual differences in brain reactivity. Thus can indicate prospective responders to symptom-related treatment in OCD and mark the relevant brain regions for effective response to treatment.