When conceptualizing age-specific onsets and sex-specific characteristics of neuropsychiatric diseases in a neurobiological context, it may be crucially important to consider differential trajectories of aging. Here, we investigated effects of age, sex, and their interactions on absolute and relative volumes of subcortical structures with known involvement in psychiatric disorders, including the basal ganglia, thalamus, hippocampus, and amygdala. Structural MRI data of 76 healthy subjects (38 males, 19–70 years) from the ICBM database were analyzed. Age-related absolute atrophy was generally found in the basal ganglia and thalamus, while in the hippocampus decline was only observed in males, and was generally absent in the amygdala. Disproportionate degeneration in the basal ganglia and thalamus, exceeding cortical decline was specific for females. When allowing higher-order models, a quadratic model could better describe the negative relation of absolute volume and age in the basal ganglia in males, and generally in the hippocampus and amygdala. We could show that negative age-relations are highly specific for certain subcortical structures in either gender. Importantly these findings also emphasize the significant impact of analytical strategies when deciding for correction of subcortical volumes to the whole-brain decline. Specifically, in the basal ganglia disproportionate shrinkage in females was suggested by the relative analysis while absolute volume analysis rather stressed an accelerating decline in older males. Given strong involvement of the basal ganglia in both cognitive aging and emotional regulation, our findings may be crucial for studies investigating the onset and prevalence of dementia and depressive symptoms in male and female aging. Hum Brain Mapp 35:238–247, 2014. © 2012 Wiley Periodicals, Inc.