In immunosuppressed individuals, the manifestation of viral pneumonia due to SARS-CoV-2 infection differs from that in healthy individuals. We reported a unique case of a 58-year-old male patient with B-cell depletion following treatment with the anti-CD20 monoclonal antibody. He presented to the Department of Pulmonary and Critical Care Medicine with complaints of intermittent fever and cough for three months, aggravated by shortness of breath for one month. He was previously diagnosed with stage IVA follicular lymphoma in April 2022 and underwent chemotherapy with Obinutuzumab (anti-CD20 monoclonal antibody). His last treatment was on November 3, 2022. On December 20, 2022, after contact with a SARS-CoV-2-infected person, he exhibited symptoms of fever peaking at 39.0 ℃, cough, and sputum production. A positive SARS-CoV-2 nucleic acid result was confirmed from a pharyngeal swab. Nine days later (December 29, 2022), the patient still had a fever. Chest CT showed multiple small pieces of ground glass opacities (GGOs) in both lower lungs. The diagnosis of viral pneumonia due to SARS-CoV-2 infection was confirmed. After five days of treatment with nirmatrelvir/ritonavir (Paxlovid) and intravenous dexamethasone (5 mg/d), his fever subsided. However, a subsequent chest CT on January 9, 2023 showed partial resorption of multiple GGOs in both lungs, accompanied by novel focal lesions. The patient developed a fever again on January 29, 2023, after which he had recurrent symptoms of fever, cough, and sputum, with intermittent short courses of antibiotics and dexamethasone, which never completely resolved. Multiple chest CTs during this period showed recurrent GGOs and consolidations in both lungs, demonstrating a migratory pattern. The patient was admitted to our hospital on March 7, 2023, with a peripheral blood test suggesting lymphocytopenia, a CD19+B lymphocyte count of zero, and negative IgG and IgM for SARS-CoV-2. A bronchoscopy and bronchoalveolar lavage fluid (BALF) analysis indicated a significantly elevated lymphocyte percentage and the presence of SARS-CoV-2 nucleic acid. Given the three-month history of chronic fever and respiratory symptoms, changing bilateral pulmonary infiltrates, and lack of SARS-CoV-2 humoral immunity, a diagnosis of persistent SARS-CoV-2 infection was considered. Subsequent treatment with Paxlovid for 15 days resulted in the resolution of all symptoms. A follow-up chest CT one month later showed almost complete normalization.