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Objective: Our objective was to retrospectively evaluate whether the levels of cell-free DNA (cfDNA) fetal fraction differed in the first trimester of pregnancies between controls and those who subsequently developed early- or late-onset fetal growth restriction (FGR). Methods: This was a case–control study conducted between May 2015 and May 2018 in 231 low-risk women who had received first trimester screening for major fetal aneuploidies (Panorama, Natera, San Carlos, CA, USA). Early- and late-onset FGR developed in 5 and 16 women, respectively, according to Delphi criteria. Multiples of median (MoM) were used to evaluate the differences in cfDNA fetal fraction between cases and controls. cfDNA fetal fraction was adjusted for gestational age (from 10 + 0 to 13 + 6 gestational weeks) and maternal weight (43–96 kg). Results: The median cfDNA fetal fractions for controls and early- and late-onset FGR were 1.00 (interquartile range [IQR] 0.89–1.12), 0.69 (IQR 0.44–0.84) and 0.93 (IQR 0.83–1.03) MoM, respectively. Statistically lower cfDNA fetal fraction MoM values were observed only in patients with early-onset FGR (Kruskal–Wallis test with Dunn post hoc test). In a 1:35 ratio (one case of early-onset FGR: 35 controls), the mean observed rank of 2.00 ± 2.23 in the cases was significantly lower than the expected 18.97 ± 10.17 (p < 0.001). Conclusions: Low-risk pregnancies that developed early-onset FGR had lower cfDNA fetal fractions than did the matched controls. This result is consistent with the placental dysfunction typical of early-onset FGR. For possible clinical use, the cfDNA fetal fraction would yield a better predictive value if adjusted for maternal weight, since maternal weight affects both cfDNA fetal fraction and the occurrence of FGR.