Abstract Prior studies have shown that both cerebrospinal fluid (CSF) concentrations of 5-hydroxyindolacetic acid (5-HIAA) and serum cortisol levels are related to overall symptom severity in depression. In the present study, 30 unmedicated inpatients meeting Research Diagnostic Criteria (RDC) criteria for depression participated in serum cortisol collection and a lumbar puncture for CSF. A multiple regression evaluated the ability of CSF 5-HIAA, serum cortisol, and age to predict cognitive and vegetative symptom clusters of the Hamilton Rating Scale for Depression. The multiple regression to predict the vegetative symptom cluster was highly significant overall ( p = 0.002) and found that age and cortisol but not 5-HIAA predicted vegetative symptoms. The regression to predict the cognitive cluster narrowly missed overall significance ( p = 0.06). Both CSF 5-HIAA and serum cortisol predicted cognitive symptoms and 5-HIAA predicted the cognitive cluster more strongly than cortisol. Age did not predict cognitive symptoms. The results suggest a dissociation between serum cortisol levels and CSF 5-HIAA in predicting vegetative and cognitive symptom clusters in depression.