Our recent data have linked plasma phospholipid fatty acid (FA) profile in patients with non-Hodgkin's lymphoma (NHL) with the clinical stage and aggressiveness of the disease. Thus, we proposed that plasma FA status in these patients may influence the effect of chemotherapy. The aim of this work was to assess FA status in NHL patients undergoing chemotherapy in relation to their response to therapy. We analyzed plasma FA profile in 47 newly diagnosed NHL patients before chemotherapy, after 3 cycles and after the end of the planned chemotherapy. Patients were treated according to the hospital protocol: 28 patients with cyclophosphamide, doxorubicin, vincristine and prednisone, 7 with other anthracycline-containing regimens, 4 patients with cyclophosphamide, vincristine and prednisone and 8 with fludarabine-based regimens. Rituximab was added in 22 patients. Ten patients who did not receive all planned chemotherapy due to death or toxicity (non-completers) had significantly lower (p < 0.05) baseline proportion of palmitoleic, linoleic, eicosapentaenoic and docosahexaenoic acid, as well as n-3 and n-6 FA, than the patients who completed chemotherapy (completers). Furthermore, the completers were divided according to the response to chemotherapy to complete remission (CR), stable disease and progressive disease (PD). Proportion of palmitic acid after the end of chemotherapy was the highest in the PD group, while stearic acid showed the opposite trend. Palmitoleic acid and all n-3 FA (18:3, 20:5, 22:5 and 22:6) were the highest in the patients in remission and the lowest in PD (p < 0.001). Linoleic acid decreased and arachidonic acid increased from the CR to the PD group (p < 0.001). These results suggest that aberrations in plasma FA may influence response to chemotherapy in patients with NHL.