Objective <p>To clarify the impact of COVID-19 infection on older frail patients, explore the immunological and inflammatory mechanisms (via peripheral blood CD8⁺ T lymphocytes and C-reactive protein [CRP]) underlying the interaction between frailty and Long COVID syndrome (LCS), identify relevant biomarkers, and validate the efficacy of antiviral combined with immune modulation therapy for improving long-term outcomes in frail patients with LCS.</p> Methods <p>A single-center prospective cohort study was conducted on older patients (≥ 60&#xa0;years) hospitalized for COVID-19 at the Second Affiliated Hospital of Soochow University between December 2022 and October 2023. Frailty was assessed using the Clinical Frailty Scale (CFS) at admission and 6-month follow-up, with evaluations by two geriatricians. Primary outcomes were all-cause mortality (in-hospital and post-discharge) and LCS incidence (per WHO definition: persistent symptoms ≥ 2&#xa0;months post-infection, Post-acute Sequelae of SARS-CoV-2 Infection [PASC] score ≥ 12). Secondary outcomes included frailty progression, length of hospital stay (LOS), oxygen therapy duration, post-discharge care needs, and readmission rate. Peripheral blood CD8 + T lymphocyte counts, CRP, interleukin-6 (IL-6), ferritin, and routine blood tests were measured within 24&#xa0;h of admission and 48&#xa0;h pre-discharge. Scores for Sequential Organ Failure Assessment (SOFA), Nutritional Risk Screening 2002 (NRS2002), and Age-Adjusted Charlson Comorbidity Index (ACCI) were calculated. Univariate/multivariate logistic regression and mediation analysis (Bootstrap, 500 iterations) were performed.</p> Results <p>Of 145 enrolled patients, 115 completed 6-month follow-up (mean age 77.2 ± 6.8&#xa0;years; 60 frail [CFS ≥ 5], 55 non-frail [CFS &lt; 5]). Compared with non-frail patients, frail patients had higher in-hospital mortality (12.0% vs 1.4%, <i>P</i> = 0.01), LCS incidence (26.7% vs 10.9%, <i>P</i> = 0.004), longer LOS (<i>P</i> = 0.004), longer oxygen therapy duration (11.3 ± 4.2 vs 7.6 ± 3.1&#xa0;days, <i>P</i> = 0.005), greater post-discharge care needs (<i>P</i> = 0.004), and higher readmission rate (<i>P</i> = 0.01). Frail patients also had lower CD8 + T lymphocyte counts at admission (<i>P</i> = 0.006) and discharge (<i>P</i> = 0.03), and higher discharge CRP (<i>P</i> = 0.01). Discharge CD8⁺ T lymphocytes were protective against frailty (OR = 0.95, 95%CI:0.93–0.98, <i>P</i> = 0.01) and frailty progression (OR = 0.98, 95%CI:0.96–0.99, <i>P</i> = 0.02), while discharge CRP was a risk factor (frailty: OR = 1.05, 95%CI:1.01–1.11, <i>P</i> = 0.04; progression: OR = 1.05, 95%CI:1.01–1.10, P = 0.02). Mediation analysis showed CD8⁺ T lymphocytes (mediation proportion = 11.4%, <i>P</i> = 0.04) and CRP (12.8%, <i>P</i> = 0.02) mediated the frailty-LCS association. In frail patients, antiviral-immune modulation therapy reduced LCS incidence (17.5% vs 45.0%, <i>P</i> = 0.03) and increased CD8⁺ T lymphocyte elevation (<i>P</i> = 0.02) vs. no therapy, with no significant benefits in non-frail patients (P &gt; 0.05).</p> Conclusion <p>Frailty is an independent risk factor for adverse outcomes (including LCS) in older COVID-19 survivors. Discharge of CD8 + T lymphocytes and CRP mediates the frailty-LCS association, and antiviral combined with immune modulation therapy may be a targeted intervention to improve prognosis in frail older patients with COVID-19.</p>