Four out of 13 drug-free relapsed schizophrenic patients improved with double-blind clonidine treatment. All responders were paranoid schizophrenic patients. Pretreatment growth hormone (GH) response to the clonidine challenge test (CCT) correlated significantly with clonidine treatment improvement in psychosis, anxiety, and negative symptom ratings. Spontaneous GH peaks following placebo correlated significantly with the behavioral change with clonidine treatment. Our data suggest that patients with normal or high alpha 2-receptor activity and "normal" cerebrospinal fluid (CSF) norepinephrine (NE) are likely to respond to clonidine treatment. Patients with either high or low CSF NE levels did not respond to clonidine treatment. CSF NE and 3-methoxy-4-hydroxyphenylglycol (MHPG) decreased significantly with clonidine treatment. Changes in CSF NE and MHPG did not correlate significantly with improvement in psychosis, but they correlated with changes in other behaviors.