A test-negative case-control study evaluated the real-world effectiveness of nirsevimab in preventing severe RSV bronchiolitis in infants. The study, conducted in Catalonia and Andorra during the 2023–2024 RSV season, included 234 infants under 12 months old admitted with bronchiolitis and tested for RSV. The effectiveness of nirsevimab was estimated using multivariate models, comparing immunized, non-immunized, and non-eligible patients. RSV was detected in 60.2% of patients, with a significantly lower rate in immunized individuals (37% vs 75%). The estimated effectiveness of nirsevimab in preventing RSV-associated lower respiratory tract infections was 81.0%, and for preventing severe disease (need for NIV/CMV), it was 85.6%. No significant differences were observed in viral coinfections, need for NIV/CMV, or hospital stay length between immunized and non-immunized patients. The study found that nirsevimab was effective in preventing RSV-related hospitalizations and severe disease in infants, regardless of age or pre-existing conditions. Immunized patients did not show higher rates of viral coinfections or differences in clinical severity. The effectiveness was consistent across all age groups, including 3–6 month-olds, and was not replaced by other viral etiologies. The study highlights the real-world effectiveness of nirsevimab in preventing RSV bronchiolitis hospitalizations and severe disease in infants following a systematic immunization program. It also underscores the importance of immunization in reducing the burden of RSV-related hospitalizations, particularly in high-risk populations. The findings support the use of nirsevimab as a preventive measure against RSV in infants, with potential implications for public health strategies in RSV prevention.A test-negative case-control study evaluated the real-world effectiveness of nirsevimab in preventing severe RSV bronchiolitis in infants. The study, conducted in Catalonia and Andorra during the 2023–2024 RSV season, included 234 infants under 12 months old admitted with bronchiolitis and tested for RSV. The effectiveness of nirsevimab was estimated using multivariate models, comparing immunized, non-immunized, and non-eligible patients. RSV was detected in 60.2% of patients, with a significantly lower rate in immunized individuals (37% vs 75%). The estimated effectiveness of nirsevimab in preventing RSV-associated lower respiratory tract infections was 81.0%, and for preventing severe disease (need for NIV/CMV), it was 85.6%. No significant differences were observed in viral coinfections, need for NIV/CMV, or hospital stay length between immunized and non-immunized patients. The study found that nirsevimab was effective in preventing RSV-related hospitalizations and severe disease in infants, regardless of age or pre-existing conditions. Immunized patients did not show higher rates of viral coinfections or differences in clinical severity. The effectiveness was consistent across all age groups, including 3–6 month-olds, and was not replaced by other viral etiologies. The study highlights the real-world effectiveness of nirsevimab in preventing RSV bronchiolitis hospitalizations and severe disease in infants following a systematic immunization program. It also underscores the importance of immunization in reducing the burden of RSV-related hospitalizations, particularly in high-risk populations. The findings support the use of nirsevimab as a preventive measure against RSV in infants, with potential implications for public health strategies in RSV prevention.