Functional brain-imaging studies in post-traumatic stress disorder (PTSD) have suggested functional alterations in temporal and prefrontal cortical regions. Effects of psychotherapy on these brain regions have not yet been examined. Twenty civilian PTSD out-patients and 15 traumatized control subjects were assessed at baseline using psychometric ratings. Cerebral blood flow was measured using trauma script-driven imagery during 99mtechnetium hexamethyl-propylene-amine-oxime single-photon emission computed tomography scanning. All 20 out-patients were randomly assigned to treatment or wait-list conditions. Treatment was brief eclectic psychotherapy (BEP) in 16 weekly individual sessions. At baseline, greater activation was found in the right insula and right superior/middle frontal gyrus in the PTSD group than in the control group. PTSD patients treated with BEP significantly improved on all PTSD symptom clusters compared to those on the waiting list. After effective psychotherapy, lower activation was measured in the right middle frontal gyrus, compared to the PTSD patients on the waiting list. Treatment effects on PTSD symptoms correlated positively with activation in the left superior temporal gyrus, and superior/middle frontal gyrus. BEP induced clinical recovery in PTSD patients, and appeared to modulate the functioning of specific PTSD-related sites in the prefrontal cortical regions.