Studies of patients with major depression disorder (MDD) have revealed reduced hippocampal volumes, but findings have been inconsistent due to sample and measurement differences. The current study sought to measure this structure in a large sample of MDD and control subjects, using a strict measurement protocol, in order to elucidate morphological-specific volumetric differences. Forty-five subjects with treatment-resistant MDD and 26 controls underwent psychiatric assessments and brain magnetic resonance imaging (MRI). The findings of this study indicate that (1) MDD results in reduced hippocampal volume, particularly in the tail section, (2) region of interest (ROI) estimation protocols and sample characteristics may help explain volumetric differences between previous MDD studies, and (3) specific ROI atrophy in treatment-resistant depression is influenced by sex.