Insecure attachment has been linked to depression and to outcome in psychotherapy. The neural mechanisms subserving the relationship between attachment security and depression are not well understood. We have developed a method to examine attachment-related brain activity in depression. Twenty-eight women, half depressed, viewed images of their mother, a female friend, and female strangers during fMRI scanning. The effects of depression and insecure attachment were determined with whole-brain multiple linear regression of blood-oxygen-level-dependent response against subjects’ Beck Depression Inventory and Adult Attachment Interview (AAI) coherence of mind scores. Interaction effects were analyzed with ANOVA. Activity associated with depression and with insecure attachment was found in the cortico-striato-thalamic circuits of affect regulation. For early attachment (mother–friend contrast), depression scores correlated with activation of cortical and sub-cortical components of these circuits, while attachment insecurity correlated with sub-cortical activity in the same circuitry. Depression and attachment insecurity correlated with both cortical and sub-cortical activities for mother–stranger, and areas of overlap and of enhancing interactions between depression and insecure attachment were found. For late attachment (friend–stranger contrast), only cortical effects were found. Depression and attachment insecurity may be subserved by similar but distinct components of affect regulating circuits. Their interactions may explain the greater difficulty of treating depression in insecurely attached patients and suggest a contributing role for insecure attachment in depression. Further, differential sub-cortical vs cortical encoding of early vs late attachment suggests a top-down model of late attachment, potentially relevant to psychotherapeutic outcome.