In about 30-50% of patients with posttraumatic stress disorder (PTSD), symptoms persist after treatment. Although neurobiological research has advanced our understanding of PTSD, little is known about the neurobiology underlying persistence of PTSD. Two functional MRI scans were collected from 72 war veterans with and without PTSD over a 6- to 8-month interval, during which PTSD patients received trauma-focused therapy. All participants performed a trauma-unrelated emotional processing task in the scanner. Based on post-treatment symptom severity, a distinction was made between remitted and persistent patients. Behavioral and imaging measures of trauma-unrelated emotional processing were compared between the three groups (remitted patients, N=21; persistent patients, N=22; and combat controls, N=25) with repeated-measures (pre- and post-treatment) analyses. Second, logistic regression was used to predict treatment outcome. Before and after treatment, persistent patients showed a higher dorsal anterior cingulate cortex (dACC) and insula response to negative pictures compared with remitted patients and combat controls. Before treatment, persistent patients showed increased amygdala activation in response to negative pictures compared with remitted patients. The remitted patients and combat controls did not differ on the behavioral or imaging measures. Finally, higher dACC, insula, and amygdala activation before treatment were significant predictors of symptom persistence. Our results highlight a pattern of brain activation that may predict poor response to PTSD treatment. These findings can contribute to the development of alternative or additional therapies. Further research is needed to elucidate the heterogeneity within PTSD and describe how differences in neural function are related to treatment outcome. Such approaches are critical for defining parameters to customize PTSD treatment and improve treatment response rates.