Early treatment failure is still a clinical challenge despite high cure rates in Hodgkin lymphoma (HL) patients. To identify the biological risk factors predicting early treatment failure, we performed a retrospective case-control study. Forty-seven pretherapeutic serum samples were available from 47 advanced stage HL patients with early treatment failure and from 47 matched controls in complete remission. All patients were treated within German Hodgkin Study Group phase 3 trials. Matching was done according to treatment, stage, age, gender, International Prognostic Score (IPS) and histological subtype. Pretreatment serum levels of 30 cytokines, chemokines and soluble receptors were determined using immunoassays and flow cytometer based cytometric bead arrays. Only interleukin-10 serum levels were significantly associated with early treatment failure after statistical correction for multitesting (paired-sign test, p = 0.0008). In summary, pretherapeutic interleukin-10 levels are associated with early treatment failure within 12 months after the end of treatment in advanced stage HL independently from known clinical factors such as age or IPS.