•Accumulating evidence suggest that treatment with high-titer COVID-19 convalescent plasma (CCP) may be effective in immunocompromised COVID-19 patients.•Recent randomized clinical trials exploring the effectiveness of treatment with CCP in immunocompetent individuals with COVID-19. However, a simil level of evidence in selected cohorts of patients with primary or secondary impaired immune response is lacking and might be highly warranted.•Results from this case report suggest that the host T-cell specific response to SARS-CoV-2 might not be sufficient to reduce viral load in the absence of neutralizing antibodies.•Acquired immune antibodies and/or related components passively infused with CCP might have a key role in boosting the plasma recipient response to the virus and promoting complete viral clearance. Management of immunocompromised COVID-19 patients is the object of current debate. Accumulating evidence suggest that treatment with high-titer COVID-19 convalescent plasma (CCP) may be effective in this characteristic clinical scenario. A 52-years old immunocompromised female patient, previously treated with rituximab for low grade B-cell lymphoma, showed prolonged SARS-CoV-2 shedding and a long-term course of signs of severe COVID-19. A first cycle of treatment with remdesivir, a nucleotide analogue prodrug effective in inhibiting SARS-CoV-2 replication, did not provide fully and sustained clinical remission. A second hospitalization was deemed necessary after 10 days from the first hospital discharge due to recrudescence of symptoms of severe COVID-19 and the evidence of bilateral interstitial pneumonia at the chest-CT scan. Clinical and radiological findings completely disappeared after CCP administration. The viral culture confirmed the absence of SARS-CoV-2-related cytopathic effect. The clinical evaluation, performed two months after hospital discharge, was unremarkable. Findings from our case report suggest that the host T-cell specific response to SARS-CoV-2 is not sufficient to reduce viral load in the absence of neutralizing antibodies. Acquired immune antibodies and/or related components passively infused with CCP might help in boosting the plasma recipient response to the virus and promoting complete viral clearance. Independently from negative results in immunocompetent individuals, the potential effectiveness of CCP infusion in selected cohorts of patients with primary or secondary impaired immune response should be tested. Further research about mechanisms of host response in immunocompromised patients with SARS-CoV-2 infection is required.