Background and Objectives: Immunocompromised patients, who are at excess risk for herpes zoster compared to the general population, can have a lower response to vaccinations. The aim of this observational single-centre prospective study is to evaluate the immunogenicity and safety of the recombinant zoster vaccine (RZV) in adults with acquired immunodeficiency, including a subgroup of patients with Non-Hodgkin B-cell Lymphoma (NHBCL) and Chronic Lymphocytic Leukaemia (CLL), who tend to develop a lower immune response. Methods: In this study, conducted at the University Hospital of Palermo, a heterogeneous population of 72 patients aged 18 years and older was enrolled. We assessed the vaccination-induced VZV anti-glycoprotein E production testing patients' blood serum pre-vaccination (T0), at month 1 (T1), one month after the second dose (T2), and at month 6 (T3). Participants were stratified according to underlying diseases and immunosuppression status: healthy controls (n=2), patients with NHBCL and CLL (n=8), other immunocompromised patients (n=53), and patients with degenerative conditions (n=9). Results: The median age of the participants is 61 years (IQR 47-69) and the majority is female (57%); 15 of them (20%) were recruited at the time of the second dose. There was a statistically significant difference between time points in all participants, as determined by one-way ANOVA (p<0.001) and in the immunocompromised group (p<0.001). A Tukey post-hoc test revealed that antibodies response at T1 and T2 was significantly higher in comparison to baseline in all participants (T1 vs T0 and T2 vs T0; p<.001) and in the immunocompromised group (T1 vs T0 and T2 vs T0; p<.001). Conclusions: A complete RZV vaccination cycle ì significantly increased VZV gE-specific immunity in a group of patients with a wide variety of immunocompromising conditions, including those with NHBCL and CLL.