OBJECTIVE: We conducted a case-control study to evaluate whether maternal and fetal omega-3 and omega-6 essential fatty acid status play possible roles in the pathogenesis of preterm birth. STUDY DESIGN: Essential fatty acid status in blood and trophoblast tissues was measured in (1) women and their newborns with spontaneous preterm birth and (2) control women and newborns at 34 weeks' gestation (maternal blood) and at term delivery. RESULTS: Thirty-seven preterm (mean gestational age 34 weeks) and 34 control mother-baby dyads (gestational age 40 weeks) were evaluated. The maternal percent of total arachidonic acid in red blood cells and plasma was increased in preterm cases versus controls at delivery (3.8- and 1.6-fold, respectively, p < 0.05). Maternal red blood cell eicosapentaenoic acid (1.98 +/- 0.15, p < 0.0001) and omega-3/omega-6 ratios (0.58 +/- 0.22, p < 0.009) were tower in preterm cases than in controls at delivery (4.64 +/- 0.32 and 1.27 +/- 0.12, respectively). Docosapentaenoic acid, a marker of omega-3 essential fatty acid deficiency, was higher in preterm maternal red blood cells (1.26 +/- 0.18, p < 0.0001) and amnion (1.27 +/- 0.19, p < 0.001) compared with term controls (0.12 +/- 0.07 and 0.58 +/- 0.13, respectively). CONCLUSION: Women delivered preterm demonstrated higher arachidonic acid and docosapentaneoic acid levels in maternal blood and trophoblast tissue than did women delivered at term. This suggests (1) altered essential fatty acid intake or metabolism in a portion of women delivered preterm and (2); increased maternal red blood cell arachidonic acid is associated with an increased risk of preterm birth.