To determine whether there are characteristics distinguishing placebo responders from nonresponders, we studied 37 outpatients meeting DSM-III-R criteria for depression who were enrolled in controlled drug trials and 14 control subjects. Clinical data and blood samples were collected on admission and after a 7- to 10-day placebo washout. All patients experiencing a 40% drop in the Hamilton Rating Scale for Depression (HRSD) at the time of the second evaluation were considered placebo responders. There were no statistically significant differences between the two groups in clinical variables. Platelet markers distinguished the groups: Most notably, placebo nonresponders had the lowest 5-HT uptake site density values, placebo responders had intermediate values, and normal controls had the highest values. Placebo responders and placebo nonresponders had higher 5-HT uptake affinity values. No significant differences were observed among the groups in platelet 5-HT2 receptor site density or affinity values. These results suggest that platelet serotonin characteristics, but not common clinical characteristics, may distinguish depressed patients who do and do not respond to placebo.