Background: Preclinical and clinical models of depression suggest sex differences may be mediated at least in part, by differences in hormonal modulation of hypothalamic-pituitary-adrenal (HPA) axis activity. Unraveling the consequences of moderating influences from the effect of sexual dimorphism will be vital to elaborating models of pathophysiology. Methods: The current study investigated urinary free cortisol (UFC) among younger adults with mild to moderate major depressive disorder to clarify the relationship with potential demographic and clinical moderators. Results: Male patients had higher mean UFC levels than female patients. Moreover, significant interactions between age and severity were found among men, but not women. In contrast to prior findings, neither age nor severity effects on UFC levels were found among female patients. Limitations: Conclusions from the current study are limited by the absence of cortisol data from matched controls. Thus it was not possible to disentangle sex differences in baseline physiology from that of pathophysiological differences tied specifically to depression. Conclusions: Despite several methodological limitations, the interactions between sex and both age and severity in this large sample of depressed patients are suggestive of differential pathophysiology for regulation of UFC excretion, and could reflect a neuroprotective effect for estrogen among younger depressed women. © 2007 Springer-Verlag.