The substitution of omega-3 (n-3) fatty acids for omega-6 (n-6) fatty acids generates eicosanoids with diminished inflammatory effects. As the lungs of patients with cystic fibrosis (CF) are in a state of chronic inflammation in which increased amounts of eicosanoids are found, n-3 supplementation may reduce this level of inflammation and result in clinical improvement. The absorption and clinicals effects of n-3 vs. n-6 fatty acids in CF were measured in a prospective, randomized, double-blind, crossover study in which 14 patients with CF (age: 6–16 years, mean 10.5 years; baseline Shwachman-Brasfield scores: 41–88, mean 76.7) received 6 weeks of n-3 ethyl ester concentrate from menhaden oil (100–131 mg/kg/day, mean 112.8) or n-6 fatty acids from safflower oil (102–132 mg/kg/day, mean 113.3), followed by a washout period of 6 weeks, and then 6 weeks of the other supplement. Analysis by gas chromatography showed that n-3 supplementation resulted in increased eicosapentaenoic acid (20:5n-3) in platelet phospholipids, from 0.14 to 2.16%. P <0.05 and in increased docosahexaenoic acid (22:6n-3), from 1.33 to 3.72%, P <0.05. Clinical effects were evaluated at weeks 0, 6, 12, and 18, and analyzed for differences among the n-3, n-6, and washout periods. No adverse effects were reported or observed. No statistically significant differences were found (ANOVA, P >0.05) in Shwachman-Brasfield scores, sweat test, weight change, or forced expiratory volume and flow (FEV1, FEF25,75%, and FVC) percentiles. Tumor necrosis factor was not measurable in any serum sample. Serum leukotriene B4 (LTB4) levels were significantly reduced by n-3 fatty acids, mean reduction (−177 pg/mL) compared to n-6 fatty acids (+63 pg/mL) P < 0.05. These results show that both n-3 fatty acids are absorbed and incorporated into platelet phospholipids in patients with CF and reduced serum LTB4. No significant clinical differences or adverse effects were found.Pediatr Pulmonol. 1994;18:211–217. ©1994 Wiley-Liss, Inc.