OBJECTIVE: Sensory phenomena (SP) are aversive sensations driving repetitive behaviors in obsessive-compulsive disorder (OCD) and Tourette's disorder that are not well addressed by standard treatments. SP are related to the functioning of an interoceptive-sensorimotor circuit that may be modulated by the 5-HT METHODS: Of 51 participants who completed the study, 27 were assigned to receive 24 mg/day of ondansetron and 24 to receive placebo. Analyses examined changes in SP severity and, for participants with OCD, overall OCD severity from baseline to final visit. Functional MRI data were collected at both visits for analysis of intrinsic functional connectivity metrics characterizing global correlation (reflecting area "hubness") and local correlation (reflecting near-neighbor coherence). RESULTS: There were no significant differences between ondansetron and placebo in the reduction of SP or overall OCD severity in the full sample. In a subsample of participants with OCD taking concomitant serotonin reuptake inhibitors (SRIs), ondansetron was associated with a significant decrease in overall OCD severity and global connectivity of the medial sensorimotor cortex compared with placebo. Longitudinal reductions in SP severity were related to decreases in right sensorimotor hubness in both groups, and to brainstem local coherence only in participants taking ondansetron. CONCLUSIONS: There was no effect of high-dose ondansetron on SP. However, when used as an augmentation to SRIs, ondansetron reduced overall OCD severity, which may be related to changes in the "hubness" of the sensorimotor cortex. Ondansetron's ability to modulate brainstem connectivity may underlie its variable effectiveness in reducing SP.