Depression has frequently been reported to be associated with other physical diseases and changes in the cytokine system. We aimed to investigate associations between a medical history of depression, its comorbidities and cytokine plasma levels in the Bavarian Nutrition Survey II (BVS II) study sample and in patients suffering from an acute depressive episode.The BVS II is a representative study of the Bavarian population aged 13–80 years. The disease history of its 1050 participants was assessed through face-to-face interviews. A sub-sample of 568 subjects and 62 additional acutely depressed inpatients of the Max Planck Institute of Psychiatry participated in anthropometric measurements and blood sampling. Tumor necrosis factor-α (TNF-α) and soluble TNF receptor (sTNF-R) p55 and sTNF-R p75 plasma levels were measured using enzyme-linked immunosorbent assays.A history of depression was associated with a higher incidence of high blood pressure, peptic ulcer, dyslipoproteinemia, osteoporosis, allergic skin rash, atopic eczema and thyroid disease.Within the BVS II sample, participants with a history of depression differed from subjects who had never had depression with regard to sTNF-R p55 and sTNF-R p75 levels even when controlling for age, BMI and smoking status. Acutely depressed inpatients showed even higher levels of sTNF-R p55 and sTNF-R p75 than subjects in the normal population. TNF-α levels were also significantly elevated in acutely depressed patients.These results confirm earlier studies regarding the comorbidities of depression and support the hypothesis that activation of the TNF-α system may contribute to the development of a depressive disorder.