We examined the relationships between regional brain activity and anxiety in bipolar depressed patients receiving adjunctive treatment with levothyroxine. Regional brain activity was assessed with positron emission tomography and [18F]fluorodeoxyglucose in 10 euthyroid, depressed bipolar women before and after 7 weeks of adjunctive therapy with levothyroxine. The primary biological measures were relative (to global) regional radioactivity as a surrogate index of glucose metabolism in pre-selected brain regions. Relationships were assessed between regional brain activity and anxiety symptoms while controlling for depression severity. At baseline, Trait Anxiety Inventory measures covaried positively with relative brain activity bilaterally in the dorsal anterior cingulate, superior temporal gyri, parahippocampal gyri, amygdala, hippocampus, ventral striatum, and right insula; state anxiety showed a similar pattern. After treatment anxiety was improved significantly. Change in trait anxiety covaried positively with changes in relative activity in right amygdala and hippocampus. Change in state anxiety covaried positively with changes in relative activity in the hippocampus bilaterally and left thalamus, and negatively with changes in left middle frontal gyrus and right dorsal anterior cingulate. Results indicate that comorbid anxiety symptoms have specific regional cerebral metabolic correlates in bipolar depression and cannot only be explained exclusively by the depressive state of the patients.