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Placentas of obese women have low mitochondrial β-oxidation of fatty acids (FA) and accumulate lipids in late pregnancy. This creates a lipotoxic environment, impairing placental efficiency. We hypothesized that placental FA metabolism is impaired in women with obesity from early pregnancy. We assessed expression of key regulators of FA metabolism in first trimester placentas of lean and obese women. Maternal fasting triglyceride and insulin levels were measured in plasma collected at the time of procedure. Expression of genes associated with FA oxidation (FAO; ACOX1, CPT2, AMPKα), FA uptake (LPL, LIPG, MFSD2A), FA synthesis (ACACA) and storage (PLIN2) were significantly reduced in placentas of obese compared to lean women. This effect was exacerbated in placentas of male fetuses. Placental ACOX1 protein was higher in women with obesity and correlated with maternal circulating triglycerides …