This study evaluates the real-world effectiveness of nirsevimab, an antibody targeting respiratory syncytial virus (RSV), in preventing severe bronchiolitis in infants. Conducted in Catalonia and Andorra during the 2023-2024 RSV season, the test-negative case-control study included 234 patients <12 months old admitted with bronchiolitis and tested for RSV. The estimated effectiveness of nirsevimab in preventing RSV-associated lower respiratory tract infection (LRTI) was 81.0% (95% CI: 60.9–90.7), and for preventing severe disease (need for non-invasive or invasive ventilation), it was 85.6% (41.7–96.4%). No significant differences were observed in viral coinfections or clinical severity between immunized and non-immunized patients. The study provides evidence that nirsevimab is effective in preventing RSV-LRTI hospitalization and severe disease in infants, including those aged 3 to 6 months, without increasing the risk of coinfections or severity of illness.This study evaluates the real-world effectiveness of nirsevimab, an antibody targeting respiratory syncytial virus (RSV), in preventing severe bronchiolitis in infants. Conducted in Catalonia and Andorra during the 2023-2024 RSV season, the test-negative case-control study included 234 patients <12 months old admitted with bronchiolitis and tested for RSV. The estimated effectiveness of nirsevimab in preventing RSV-associated lower respiratory tract infection (LRTI) was 81.0% (95% CI: 60.9–90.7), and for preventing severe disease (need for non-invasive or invasive ventilation), it was 85.6% (41.7–96.4%). No significant differences were observed in viral coinfections or clinical severity between immunized and non-immunized patients. The study provides evidence that nirsevimab is effective in preventing RSV-LRTI hospitalization and severe disease in infants, including those aged 3 to 6 months, without increasing the risk of coinfections or severity of illness.