BACKGROUND Although both maternal respiratory syncytial virus (RSV) prefusion F vaccination (RSVpreF) and infant nirsevimab immunization have been approved for the prevention of RSV lower respiratory tract infections, the 2 have not been evaluated in a single study, and their sequential administration has not been studied systematically. METHODS We performed a prospective, randomized, open-label, phase 4 study at 8 US sites of mother-infant pairs randomized 1:1:1:1 during pregnancy: maternal RSVpreF vaccine alone, maternal RSVpreF vaccine/infant nirsevimab at birth, maternal RSVpreF vaccine/infant nirsevimab at 3 months, or infant nirsevimab alone at birth. We are following the mother-infant pairs for 12 months to ascertain safety, infant tolerability, and the magnitude and durability of RSV-A and -B neutralizing antibodies (nAbs). We report interim data from September 19, 2024, to May 15, 2025, including 4-month infant follow-up. RESULTS In total, 181 mothers were enrolled. Both products alone and in combination were safe. No related serious adverse events were observed in mothers or infants. Nirsevimab was well tolerated, and all local and systemic reactogenicity was mild to moderate in severity. RSVpreF vaccination boosted maternal RSV-A nAb titers 17.35-fold at the time of delivery, and titers were durable through 3 months postdelivery. The geometric mean transfer ratio of RSV-A nAbs was higher than 1.3 and similar across groups. RSV nAbs were highly elevated in infants at 6 weeks and 3 months, irrespective of group, with modest differences in waning. CONCLUSIONS Maternal RSVpreF vaccine and infant nirsevimab administration, either alone or in combination, were safe and provided high RSV nAb titers in infants through interim follow-up.