ABSTRACT Preeclampsia affects up to 4% of pregnancies and is marked by the development of hypertension and proteinuria after 20 weeks of gestation. Complications associated with the disorder include preterm birth, fetal growth restriction, placental abruption, HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome, seizures, and other end organ damage. Aspirin has been shown to reduce the incidence of preterm preeclampsia by 62%. However, it can also lead to peripartum bleeding. Screening for preeclampsia in the first trimester (11 to 13 weeks' gestation) can help identify up to 60% of pregnant individuals who will develop preterm preeclampsia. If preeclampsia screening is conducted during this first trimester, aspirin can be initiated earlier and discontinued earlier to mitigate the risk of peripartum bleeding. In addition, increased soluble fms-like tyrosine kinase-1 to placental growth factor (sFlt-1:PlGF) ratio is associated with preeclampsia weeks before its clinical onset. An sFlt-1:PlGF of ≤38 has been shown to accurately exclude preeclampsia in pregnant individuals with suspected disease. The aim of this study was to compare the effect of discontinuing aspirin in pregnant individuals at 24 and 28 weeks' gestation with a normal sFlt-1:PlGF ratio of ≤38 against those who continued aspirin treatment until 36 weeks of gestation. This was an open-label, randomized, noninferiority trial conducted at 9 maternity hospitals in Spain. Included were adult individuals with singleton pregnancies who had live births, were found to be at high risk of preeclampsia at the first-trimester screening, and a normal sFlt-1:PlGF between 24 and 28 weeks of gestation. Participants were randomly assigned 1:1 to discontinue aspirin (intervention group) or continue aspirin treatment (control group). The primary outcome was delivery due to preterm preeclampsia (before 37 weeks' gestation). Noninferiority was met if the higher 95% confidence interval (CI) for the difference in the incidences of preterm preeclampsia between the 2 groups was <1.9%. A total of 964 pregnant individuals, who were identified as high-risk for preterm preeclampsia and prescribed 150 mg of aspirin daily at bedtime, were eligible for the analysis. The rates of preterm preeclampsia in the intervention and control groups were 1.48% and 1.73%, respectively (absolute difference, −0.25% 95% CI, −1.86% to 1.36%). In conclusion, the threshold for noninferiority was not met. In pregnant individuals at high risk of preeclampsia and a normal sFlt-1:PlGF ratio of ≤38, discontinuing aspirin at 24 to 28 weeks' gestation was noninferior to continuing aspirin until 36 weeks to prevent preterm preeclampsia.