Fibromyalgia (FM) is a chronic, common pain disorder characterized by widespread, pervasive pain-related symptomatology and high levels of negative affect. Cognitive-behavioral therapy (CBT) may foster improvement in FM symptoms via reductions in pain-related catastrophizing (a negative, pain-amplifying cognitive/emotional process). In this randomized controlled trial, we investigated the effect of CBT on clinical improvement and catastrophizing-specific brain circuitry. Adult women with FM were randomized to one of the two 8-week interventions: CBT (N=64) or education control (EDU, N=34) (ratio=2:1). Clinical symptoms (pain severity and interference, pain catastrophizing) and brain response to a pain catastrophizing task were assessed before and after the intervention. Compared to EDU, CBT significantly reduced pain interference (CBT=-1.2± 1.7, P<0.0001; EDU=-0.2± 2.0, P=0.59; PCBTvsEDU<0.05) and pain catastrophizing (CBT=-8.9± 9.3, P<0.0001; EDU=-4.6± 9.1, P=0.01; PCBTvsEDU<0.05), but not pain severity (CBT=-0.6± 1.5, P<0.01; EDU=0.0± 1.7, P=0.91; PCBTvsEDU=0.12). Importantly, reductions in pain catastrophizing mediated the group differences in pain improvement. Brain fMRI identified the ventral posterior cingulate cortex (vPCC) as activated during a focused pain catastrophizing task. Interestingly, vPCC, normally a key region of the default mode network (DMN) was anti-correlated with the DMN and positively correlated with sensorimotor and salience network subregions during pain catastrophizing. CBT, compared to EDU, decreased vPCC-to-M1 (primary motor cortex) connectivity. In summary, we found a significant therapeutic effect of CBT on FM symptom improvement, along with a CBT-produced change in the neural circuitry contributing to pain and catastrophizing in women with fibromyalgia. National Center for Complementary and Integrative Health (R01-AT007550, R61-AT009306, P01-AT006663), National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01-AR064367), and the National Center for Research Resources (P41RR14075, S10RR021110, S10RR023043).