The present randomised placebo controlled trial explored the extent to which osteopathic manipulative treatment (OMT) affects brain activity, particularly the insula, during both an "interoceptive awareness" and "exteroceptive awareness" task in a sample of 32 right-handed adults with chronic Low Back Pain (CLBP) randomly assigned to either the OMT or sham group. Patients received 4 weekly sessions and fMRI was performed at enrolment (T0), immediately after the first session (T1) and at 1 month (T2). The results revealed that the OMT produced a distinct and specific reduction in BOLD response in specific brain areas related to interoception, i.e., bilateral insula, ACC, left striatum and rMFG. The observed trend across the three time points appears uncharacteristic. At T1, a marginal increase of the BOLD response was observed in all the above-mentioned areas except the rMFG, which showed a decrease in BOLD response. At T2, the response was the opposite: areas related to interoception (bilateral insula and ACC) as well as the rMFG and left striatum demonstrated significant decreased in BOLD response. The findings of this study provide an insight into the effects of manual therapies on brain activity and have implications for future research in the field.