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Background Malaria during pregnancy can cause serious consequences including maternal anemia and low birthweight (LBW). Routine antenatal care (ANC) in Rwanda includes malaria symptom screening at each ANC visit. This cluster randomized controlled trial investigated whether adding intermittent screening with a malaria rapid diagnostic test at each routine ANC visit and treatment of positives during pregnancy (ISTp) is more effective than routine ANC for reducing malaria prevalence at delivery. Methods Between September 2016 and June 2018, pregnant women initiating ANC at 14 health centers in Rwanda were enrolled into ISTp or control arms. All women received an insecticide-treated bed net at enrollment. Hemoglobin concentration, placental and peripheral parasitemia, newborn outcome, birthweight, and prematurity were assessed at delivery. Results Nine hundred seventy-five women were enrolled in ISTp and 811 in the control group. Routine ANC plus ISTp did not significantly reduce polymerase chain reaction–confirmed placental malaria compared to control (adjusted relative risk [aRR], 0.94 [95% confidence interval {CI},.59–1.50]; P =.799). ISTp had no impact on anemia (aRR, 1.08 [95% CI,.57–2.04]; P =.821). The mean birthweight of singleton newborns was not significantly different between arms (3054 g vs 3096 g, P =.395); however, women in the ISTp arm had a higher proportion of LBW (aRR, 1.59 [95% CI, 1.02–2.49]; P =.042). Conclusions This is the only study to compare ISTp to symptomatic screening at ANC in a setting where intermittent preventive treatment is not routinely provided. ISTp did not reduce the prevalence of malaria or anemia at delivery and was associated with an increased risk of LBW. Clinical Trials Registration NCT03508349. [ABSTRACT FROM AUTHOR]