Objective: This study investigated whether cancer patients with and without major depression exhibit immune system abnormalities similar to those reported in medically healthy, depressed subjects without cancer. Method: The study subjects consisted of patients diagnosed with pancreatic, esophageal, or breast cancer. Other groups consisted of subjects with major depression (without cancer) and healthy comparison subjects. Subjects' diagnoses were made with the Structured Clinical Interview for DSM-III-R. Severity of depression was measured with the Hamilton Depression Rating Scale. Plasma concentrations of interleukin-6 (IL-6) and postdexamethasone cortisol were measured. Results: Cancer patients with depression had markedly higher plasma concentrations of IL-6 than healthy comparison subjects and cancer patients without depression. Although significant correlations were found between Hamilton depression scale scores and plasma concentrations of postdexamethasone cortisol, no significant correlations were found between plasma IL-6 and postdexamethasone cortisol concentrations. Conclusions: Higher than normal plasma IL-6 concentrations were associated with a diagnosis of major depression in cancer patients. IL-6 may contribute to sickness behavior that has overlapping symptoms with major depression.