Rituximab (RTX), a chimeric anti-CD20 monoclonal antibody, is widely used for B-cell malignancies and autoimmune diseases, but its B-cell–depleting effect may lead to clinically relevant secondary immunodeficiency. Although B-cell recovery usually occurs within 6–12 months, some patients develop prolonged immune dysfunction, including hypogammaglobulinemia, late-onset neutropenia, impaired vaccine responses, and increased susceptibility to bacterial, viral, and opportunistic infections. About 10–40% of adults and up to 50% of children recipients develop hypogammaglobulinemia; the main risk factors are chronic RTX exposure, low baseline IgG, and concurrent immunosuppression. Persistent IgG deficiency (< 5 g/L) is associated with recurrent bacterial and opportunistic infections and may reveal previously unrecognized inborn errors of immunity (IEI). This review summarizes the clinical spectrum of RTX-associated immunodeficiency and discusses practical strategies for risk mitigation, including baseline viral screening, immunoglobulin assessment, vaccination planning, longitudinal monitoring, immunoglobulin replacement, and RTX dose modification.