Serotonin receptor changes have been associated with the pathophysiology and treatment of major depression. Only one other study has investigated serotonin receptor changes in older depressed patients. We used positron emission tomography (PET) and [18F]altanserin, a ligand with high affinity for the 5-HT(2A) receptor, to examine the relationship between 5-HT(2A) receptor density and depression. Depressed subjects (n = 16), age > 50 years, were recruited as part of a larger study. Older depressed subjects consisted of early-onset recurrent depression (EORD, n = 11) and late-onset depression (LOD, n = 5). An age-matched control group (n = 9) was also recruited. All subjects were right-handed, nonsmokers and antidepressant-free. Regions of interest were determined on a summed MPRAGE scan transformed into Talairach space and coregistered with the PET images. Depressed subjects had less hippocampal 5-HT(2A) receptor binding than controls (p = 0.05). No significant differences in receptor binding were found between EORD and LOD subjects. Depressed subjects not previously treated for depression (n = 6) had less hippocampal 5-HT(2A) receptor binding (p = 0.04) than previously treated subjects (n = 10). It may be that prior medication treatment provides a compensatory upregulation of the 5-HT(2A) receptor.