A 45-year-old man with severe antiphospholipid syndrome and diffuse alveolar hemorrhage was hospitalized with fever and diagnosed with SARS-CoV-2 infection. He received remdesivir and was discharged after 5 days. During quarantine, he was hospitalized three times for abdominal pain and once for fatigue and dyspnea, with hypoxemia and suspected recurrent diffuse alveolar hemorrhage. SARS-CoV-2 RT-PCR cycle threshold (Ct) values increased to 37.8, suggesting resolving infection. However, on day 72, RT-PCR was positive again with a Ct value of 27.6, indicating a recurrence. He received another course of remdesivir, and subsequent tests were negative. On day 105, he was admitted for cellulitis, and hypoxemia developed, requiring high-flow oxygen. His immunosuppression was escalated, and he received remdesivir again. On day 143, RT-PCR Ct value was 15.6, indicating a third recurrence. He received a SARS-CoV-2 antibody cocktail and later required intubation due to hypoxemia. A bronchoalveolar-lavage specimen showed SARS-CoV-2 RNA and Aspergillus fumigatus. He died from shock and respiratory failure. Quantitative viral load assays confirmed RT-PCR results, with peak levels at 8.9 log10 copies per milliliter. Tissue studies showed highest SARS-CoV-2 RNA levels in the lungs and spleen. Phylogenetic analysis showed persistent infection and accelerated viral evolution. Amino acid changes were predominantly in the spike gene and receptor-binding domain. Infectious virus was confirmed in nasopharyngeal samples from days 75 and 143. Immunophenotyping and SARS-CoV-2-specific B-cell and T-cell responses were analyzed. This case highlights the potential for persistent SARS-CoV-2 infection and accelerated viral evolution in immunocompromised individuals. The patient's prolonged infection and viral evolution suggest that immunocompromised individuals may be at higher risk for persistent infection and viral adaptation. The case underscores the importance of monitoring and managing SARS-CoV-2 in immunocompromised patients.A 45-year-old man with severe antiphospholipid syndrome and diffuse alveolar hemorrhage was hospitalized with fever and diagnosed with SARS-CoV-2 infection. He received remdesivir and was discharged after 5 days. During quarantine, he was hospitalized three times for abdominal pain and once for fatigue and dyspnea, with hypoxemia and suspected recurrent diffuse alveolar hemorrhage. SARS-CoV-2 RT-PCR cycle threshold (Ct) values increased to 37.8, suggesting resolving infection. However, on day 72, RT-PCR was positive again with a Ct value of 27.6, indicating a recurrence. He received another course of remdesivir, and subsequent tests were negative. On day 105, he was admitted for cellulitis, and hypoxemia developed, requiring high-flow oxygen. His immunosuppression was escalated, and he received remdesivir again. On day 143, RT-PCR Ct value was 15.6, indicating a third recurrence. He received a SARS-CoV-2 antibody cocktail and later required intubation due to hypoxemia. A bronchoalveolar-lavage specimen showed SARS-CoV-2 RNA and Aspergillus fumigatus. He died from shock and respiratory failure. Quantitative viral load assays confirmed RT-PCR results, with peak levels at 8.9 log10 copies per milliliter. Tissue studies showed highest SARS-CoV-2 RNA levels in the lungs and spleen. Phylogenetic analysis showed persistent infection and accelerated viral evolution. Amino acid changes were predominantly in the spike gene and receptor-binding domain. Infectious virus was confirmed in nasopharyngeal samples from days 75 and 143. Immunophenotyping and SARS-CoV-2-specific B-cell and T-cell responses were analyzed. This case highlights the potential for persistent SARS-CoV-2 infection and accelerated viral evolution in immunocompromised individuals. The patient's prolonged infection and viral evolution suggest that immunocompromised individuals may be at higher risk for persistent infection and viral adaptation. The case underscores the importance of monitoring and managing SARS-CoV-2 in immunocompromised patients.