To analyze cytokine responses and the clinical course of septic neonates orally supplemented with docosahexaenoic acid as well as to evaluate fatty acid incorporation into leukocytes. A quasiexperimental study was conducted in neonates who developed sepsis following a surgical procedure. Selected neonates were randomly assigned to receive 100 mg docosahexaenoic acid (G-DHA) daily or olive oil (G-OO) as placebo for 14 d throughout a sepsis episode. At selection (baseline), blood samples were obtained to determine interleukin-1 (IL-1)β, interleukin-6 (IL-6), and tumor necrosis factor-α as well as the leucocyte fatty acid profile. Measurements were repeated at 7 (D7) and 14 d (D14) of follow-up. Within- and between-group comparisons were conducted with parametric statistics after logarithmic transformation. Repeated measurement analyses with a general linear model procedure were used, adjusting according to human milk intake, use of anti-inflammatory drugs, and nutritional status. Sixty-three neonates were included: 29 in G-DHA group and 34 in G-OO group. Although decreases of cytokines during hospitalization were similar in both groups, there was a greater decrease of IL-1β in the G-DHA group than in the G-OO group after adjusting by confounders (P = 0.028). Leukocyte docosahexaenoic acid increased from 4.96 ± 2.96 at baseline to 5.52 ± 3.05 and 5.92 ± 2.8 at D7 and D14, respectively, in the G-DHA group (P = 0.044). Illness severity was inversely associated with the proportion of docosahexaenoic acid in leukocytes throughout follow-up (P = 0.034). Oral supplementation with docosahexaenoic acid to neonates attenuates IL-1β response and the clinical course of sepsis. This may be an additional strategy to further benefit ill neonates even if they are not candidates for parenteral nutrition. Copyright © 2012 Elsevier Inc. All rights reserved.