We report real world use over time in immunocompromised subjects receiving tixagevimab/cilgavimab (T/C) pre-exposure prophylaxis (PrEP). Observational study on participants receiving T/C PrEP stratified: never had COVID-19 (NoC), hybrids (H) and breakthrough infections (BTIs) if COVID-19 before or after PrEP, respectively. Anti-RBD IgG and BA.5 neutralizing antibodies (nAbs), mucosal IgG, T-cell immunity at the administration of T/C (T0), 3 (T1), 6 (T2), and 9 (T3) months after, were measured. Comparison of markers in each group across timepoints, Poisson regression model for BTIs incidence rate ratios were performed. N=231 participants: median age 63 years (IQR 54.0-73.0), 84% hematological disease, median vaccine dose of three. N=72 NoC, 103 H and 56 (24%) BTIs, mostly mild/moderate, IR 4.2 (95%CI 3.2-5.4) BTIs/100 patients-months, no factors associated with. A significant increase of anti-RBD IgG at T1 was observed in all the groups, with a decline at T2. GMTs of anti-BA.5 nAbs were low at T1 for all the groups and around/below the cut off. No changes of IFN-γ. Overall, a mucosal response was observed at T1. An incidence of 24% of mild/moderate BTIs was observed. Anti-RBD IgG levels persistence was ensured, BA.5 nAbs were low/undetectable, cellular T immunity remained stable.