Objective: Knowledge regarding the emotional and physiologic response of women with psychiatric disorders undergoing in vitro fertilization (IVF) treatments is rather limited. We evaluated psychological adjustment and cortisol reactivity to IVF treatment in women with a lifetime diagnosis of a unipolar mood or anxiety disorder compared to those without such a diagnosis. Method: Women undergoing IVF treatments (N = 121) were interviewed from January 2006 to December 2007 to assess for the presence of a history of a lifetime DSM-IV-TR unipolar mood or anxiety disorder. They were evaluated prospectively at baseline, at ovulation, and before the pregnancy test. Primary outcome measures included assessments of depressive and anxiety symptoms (Center for Epidemiologic Studies Depression Scale and State-Trait Anxiety Inventory, respectively) and plasma cortisol levels. Results: Of 108 participants included in the study, 19.4% (n = 21) were determined to have a lifetime Axis I unipolar mood or anxiety diagnosis. Women with lifetime Axis I psychopathology showed significantly greater symptom elevation for depression (F2,194 = 10.97, P < .001) and for anxiety (F2,194 = 3.4813, P = .033) compared to the group without psychopathology. A different physiologic pattern was observed for cortisol response: whereas the group without psychopathology responded physiologically to the stressful treatment with continuously elevated cortisol levels, a blunted cortisol response was observed for the group with lifetime psychopathology (F2,200 = 2.9, P = .05). Conclusions: Women diagnosed with a lifetime unipolar mood or anxiety disorder developed robust symptom exacerbation during IVF treatment compared to women without an Axis I diagnosis. Conversely, the women with a lifetime diagnosis are characterized by a blunted cortisol response, indicating a pattern of dissociation between the robust increase in anxiety and depression and cortisol response to the acute psychological stress. This study emphasizes the need for a psychiatric screening prior to IVF treatment and for the utilization of preventive psychiatric and psychological interventions.