Background: The SARS-CoV-2 infection is now a part of the everyday lives of immunocompromised patients, but the choice of treatment and the time of viral clearance can often be complex, exposing patients to possible complications. The role of the available antiviral and monoclonal therapies is a matter of debate, as are their effectiveness and potential related adverse effects. To date, in the literature, the amount of data on the use of combination therapies and on the multiple lines of anti-SARS-CoV-2 therapy available to the general population and especially to inborn error of immunity (IEI) patients is small. Methods: Here, we report a case series of five adult IEI patients managed as inpatients at three Italian IEI referral centers (Rome, Treviso, and Cagliari) treated with combination therapy or multiple therapeutic lines for SARS-CoV-2 infection, such as monoclonal antibodies (mAbs), antivirals, convalescent plasma (CP), mAbs plus antiviral, and CP combined with antiviral. Results: This study may support the use of combination therapy against SARS-CoV-2 in complicated IEI patients with predominant antibody deficiency and impaired vaccine response.