The aim of this study was to verify whether pretreatment plasma levels of vascular endothelial growth factor (VEGF) correlate with prognosis and survival of patients with diffuse large B-cell lymphoma (DLBCL). Plasma VEGF levels were assessed at the time of diagnosis in 157 DLBCL patients treated with anthracycline-based chemotherapy. Plasma VEGF levels greater than or equal to the highest quartile (high VEGF levels) were associated with lower probability of a complete remission achievement (odds ratio 0.3; 95% confidence interval [CI]: 0.1-0.6; p = 0.002) in univariate as well as in multivariate analysis (p = 0.04). The estimated 3-year progression-free survival (PFS) rate of patients with high VEGF levels was 31.7% (95% CI 17-51) compared to the 62.5% 3-year PFS rate (95% CI 53-71; p = 0.0004) in the patients with lower values. The former group of patients demonstrated an estimated 3-year overall survival (OS) rate of 47.1% (95% CI 30-65) in contrast to the 3-year OS rate of 64.3% (95% CI 54-73; p = 0.02) in the latter. In multivariate analysis, the high VEGF level retained its independent impact on shorter PFS (p = 0.02). Our results suggest that VEGF plays an important role in the clinical course of DLBCL. VEGF may be a useful marker for selecting the patients for whom new treatment approaches, especially those based on VEGF inhibitors, could be recommended.