Strong evidence indicates that tumor growth can be actively controlled by the immune system, and interleukins (ILs) are known to play an influential role in immune response regulation. Moreover, inflammatory cytokines are significantly involved in lymphoma pathogenesis. We aimed to investigate serum levels of IL-4 and IL-18 in aggressive non-Hodgkin's lymphoma (A-NHL) patients and their relationship with prognostic parameters and therapy outcome. These serum factors were measured by enzyme-linked immunosorbent assay in 46 patients with pathologically verified A-NHL before and after chemotherapy, and in 20 healthy controls. No significant difference in serum IL-4 (P = 0.11) and IL-18 (P = 0.261) levels was observed between the A-NHL and controls groups. None of the prognostic parameters analyzed significantly correlated with serum IL-4 concentration, while only lactate dehydrogenase (LDH) measurements were associated with IL-18 values. Serum IL-18 was elevated in the patients with high LDH levels compared to those exhibiting normal values (P = 0.045). In addition, no correlation was found between the concentrations of serum IL-4 and IL-18 in A-NHL patients (r = 0.188, P = 0.187). While IL-18 values did not change, serum IL-4 levels decreased following chemotherapy, independently from treatment response (P = 0.002). Our study is the first to report the response of serum IL-4 levels to chemotherapy. In conclusion, although IL-4 serum concentration has no diagnostic role, it is sensitivite to standard chemotherapy in A-NHL. However, serum IL-18 measurements have no diagnostic or prognostic role in this disease.