Although standard clinical prognostic factors predict outcome in diffuse large B-cell lymphoma (DLBCL), predicting the outcome of patients might be further refined using biological factors. We tested whether serum cytokines could provide prognostic information in DLBCL patients. Thirty cytokines were measured in pretreatment samples from newly diagnosed DLBCL patients using a multiplex ELISA. Sixty-nine patients treated with R-CHOP plus epratuzumab were used in an initial cohort and 185 patients treated with standard R-CHOP served as a subsequent validation cohort. In the initial cohort, elevated serum interleukin-10 [IL-10; hazard ratio (HR) = 6.6, P = 0.022], granulocyte macrophage colony-stimulating factor (HR = 10.8, P= 0.027) and IP-10 (interferon-inducible protein-10, CXCL10; HR = 3.32, P = 0.015) were associated with event-free survival (EFS). An identical analysis of the subsequent validation cohort confirmed that elevated serum levels of IP-10 were strongly associated with a poor EFS (HR = 2.42, P = 0.0007); and also identified interleukin-8 (IL-8; HR = 3.40, P = 0.00002) and interleukin-2 receptor (IL-2R, CD25; HR = 2.59, P = 0.0012) as significantly associated with prognosis. The prognostic significance of elevated IP-10 remained significant after adjustment for the International Prognostic Index (EFS - HR 1.99, P = 0.009, overall survival-HR 1.93, P = 0.021). Elevated pretreatment serum IP-10 levels are therefore associated with an increased likelihood of disease relapse and an inferior survival in patients with DLBCL.