BACKGROUND: A novel nutritional formula (NNF) enriched in eicosapentaenoic (EPA) and gamma-linolenic fatty acids and antioxidants reduces airway inflammation and improves clinical outcomes in critically ill patients, but NNF has not been evaluated in chronic inflammatory diseases such as persistent asthma. OBJECTIVE: To evaluate the efficacy, compliance, and safety of NNF in asthmatic children. METHODS: Children, 6-14 years of age, with mild to moderate persistent asthma, on as needed albuterol alone, were randomized to receive daily NNF (n=23) or control formula (n=20) for 12 weeks, with multiple assessments of asthma control, spirometry, measures of airway inflammation, formula tolerance, and adverse events. RESULTS: Daily consumption of either NNF or a control formula showed improvement in asthma-free days over time (P=0.04) but there was no difference between groups. However, the NNF group had lower exhaled nitric oxide levels compared with the control group at weeks 4, 8, and 12 (P<0.05). An overall group difference in log FEV1 PC20 (P=0.05) was found in favour of the NNF group as well. Significantly higher levels of EPA in plasma (P<0.01) and peripheral blood mononuclear cell (PBMC) (P<0.01) phospholipids in the NNF group compared with control group within 2 weeks indicated good adherence with daily NNF intake. There were no differences in adverse events for NNF vs. control after 12 weeks. CONCLUSIONS: Both NNF and control groups demonstrated improvement in asthma-free days. NNF-treated group had reduced biomarkers of disease activity. Rapid PBMC fatty acid composition changes reflected an anti-inflammatory profile. Dietary supplementation with NNF was safe and well tolerated (ClinicalTrials.gov number NCT01087710).