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Nirsevimab is a long-acting monoclonal antibody designed to prevent infections due to respiratory syncytial virus (RSV). Here we report on a retrospective, multicenter study encompassing a total of 19 Italian neonatal and pediatric centers evaluating the epidemiology of lower respiratory tract infection (LRTI)-related hospitalizations in infants younger than 2 years during the first RSV season following the introduction of nirsevimab prophylaxis. A total of 401 hospitalizations were reported, with 40.4% being in children with previous prophylaxis with nirsevimab. Respiratory syncytial virus was the most frequently identified pathogen (47.5%), followed by rhinovirus/enterovirus (20.2%) and human metapneumovirus (hMPV; 6.9%). In multivariable analyses adjusted for age, sex, and month of diagnosis, prior nirsevimab immunization was associated with a significantly reduced likelihood of RSV-related hospitalization (adjusted odds ratio [aOR], 0.259; 95% CI, 0.157-0.427), corresponding to an estimated effectiveness of 74.1% (95% CI, 57.3-84.3). Conversely, nirsevimab-immunized infants showed increased odds of hospitalization due to hMPV (aOR, 2.490; 95% CI, 1.019-6.085) and rhinovirus/enterovirus (aOR, 2.573; 95% CI, 1.424-4.650). Lower respiratory tract infections associated with hMPV predominantly occurred outside the typical RSV season, being associated with moderate-to-severe clinical presentations. These findings confirm the real-world effectiveness of nirsevimab against RSV hospitalizations, also highlighting the need for the continued surveillance of non-RSV respiratory pathogens in the context of universal RSV immunoprophylaxis.