Advanced age, comorbidities, and immunocompromised states remain major risk factors for severe or persistent COVID-19 despite vaccination and antivirals, underscoring the need for innovative treatments such as adoptive T-cell therapy (ATT). In this prospective single-center study, we evaluated the safety, feasibility, and efficacy of two ATT approaches in immunocompromised patients with high-risk or persistent SARS-CoV-2 infection: interferon-γ cytokine capture system virus-specific T cells (IFN-γ CCS VST, n = 12; median age 59) and CD45RA + T-cell depleted donor lymphocyte infusion (CD45RA⁺ TCD DLI, n = 11; median age 46). Most patients (73.9%) had undergone prior hematopoietic stem cell transplantation (HSCT). Both treatments were safe, with no adverse events observed. One-year overall survival (OS) did not differ significantly between groups (p = 0.8907 overall; p = 0.5907 in HSCT recipients). However, CD45RA⁺ TCD DLI showed a trend toward improved 1-year COVID-19–free survival (p = 0.058) and significantly better survival among HSCT recipients (p = 0.0362). Viral clearance was achieved in most patients (90.9% vs. 83.3%). Immunomonitoring revealed distinct immune dynamics: between weeks 5–8, IFN-γ CCS VST promoted naïve T-cell expansion with broad cytokine elevation, while CD45RA⁺ TCD DLI expanded memory T cells with a more restricted cytokine profile. IFN-γ CCS VST also elicited stronger in vivo expansion of SARS-CoV-2–specific CD4 + and CD8 + T cells. In summary, both ATT approaches are safe and effective in immunocompromised patients with persistent COVID-19. CD45RA⁺ TCD DLI, which can be generated from convalescent donors as an off-the-shelf product, may provide a practical strategy for pandemic preparedness and treatment of vulnerable patients with immune senescence.