BackgroundRespiratory syncytial virus (RSV) is the leading cause of acute lower respiratory infections (ALRI) in infants younger than 6 months globally. A maternal bivalent RSV prefusion F (RSVpreF) vaccine was introduced to the UK in late summer in 2024 (August 12 in Scotland and September 1 in England), with all pregnant women at 28 weeks or more of gestation eligible for vaccination. We aimed to understand RSVpreF vaccine effectiveness in a real-world setting.MethodsWe conducted a multicentre, test-negative, case-control study to analyse the vaccine effectiveness of maternal RSVpreF vaccination against the primary outcome of hospitalisation (ie, admission to hospital) for RSV-associated ALRI in infants. Patient and public involvement from a group of parents informed the study protocol design. Included patients were infants with ALRI born after Aug 12, 2024 (Scotland), and Sept 1, 2024 (England), and therefore had mothers eligible for maternal vaccination, who were admitted to 30 hospital sites across the UK from Sept 30, 2024, to Jan 20, 2025, and tested for RSV. Infants were followed up until hospital discharge or death as an inpatient. Primary vaccine effectiveness of maternal RSVpreF vaccination against RSV-associated hospitalisation was calculated with the use of a conditional logistic regression adjusted by site, calendar month of hospital attendance for the infant, age, preterm birth, and sex.FindingsWe included 537 mother–infant pairs, in whom there were 391 RSV-positive infant cases (median age 1·63 months [IQR 0·94–2·26]) and 146 RSV-negative infant controls (1·41 months [0·77–2·03]). Of 537 recruited infants, 297 (55%) were male and 240 (45%) were female. Ethnicity data were available for 533 mothers, of whom 434 (81%) self-identified as White. The mothers of 73 (19%) RSV-positive cases and 60 (41%) RSV-negative controls had received RSVpreF vaccine before delivery. The adjusted effectiveness of maternal RSVpreF vaccination for preventing infant hospitalisation was 58% (95% CI 28–75) for infants whose mothers were vaccinated at any time before delivery and 72% (48–85) for infants whose mothers were vaccinated more than 14 days before delivery (39 [11%] of 357 RSV-positive cases vs 43 [33%] of 129 RSV-negative controls).InterpretationIn the real-world setting of the first season of vaccine implementation in England and Scotland, maternal RSVpreF vaccination was effective and equivalent to trial settings in reducing the risk of hospitalisation in infants with RSV-associated ALRI.