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Abstract Background The safety of Paxlovid and Molnupiravir in COVID-19 patients with autoimmune diseases remains unclear, particularly concerning the risk of interstitial lung disease (ILD). Objective To evaluate the risk of developing ILD among COVID-19 patients with autoimmune diseases treated with Paxlovid or Molnupiravir. Design Retrospective cohort study. Setting Data were Based on data from the US Collaborative Network in TriNetX Patients: 18,384 COVID-19 patients with pre-existing autoimmune diseases. Interventions Treatment with Paxlovid or Molnupiravir within five days of COVID-19 diagnosis. Measurements ILD diagnosis confirmed by ICD-10-CM codes and radiographic evidence. Results ILD occurred in 54 patients in the Paxlovid group and 79 patients in the Molnupiravir group (HR: 0.73, 95% CI: 0.52–1.03), indicating no statistically significant difference. Subgroup analyses by age, sex, and race showed consistent results. Limitations Observational design limits causal inference; potential residual confounding. Conclusion Treatment with Paxlovid or Molnupiravir does not significantly increase ILD risk in COVID-19 patients with autoimmune diseases. Primary Funding Source Chung Shan Medical University Hospital. Registration Not applicable. Key messages What is already known on this topic The safety of COVID-19 antiviral treatments, particularly nirmatrelvir-ritonavir (Paxlovid) and Molnupiravir, in patients with autoimmune diseases has been poorly understood. Patients with autoimmune conditions are considered high-risk due to compromised immune systems and potential susceptibility to complications like interstitial lung disease (interstitial lung disease) . Previous studies have generally excluded or underrepresented patients with autoimmune diseases, creating a significant knowledge gap regarding the safety of these treatments for this vulnerable population. What this study adds This study provides evidence that there is no statistically significant difference in the risk of developing interstitial lung disease between COVID-19 patients with autoimmune diseases treated with nirmatrelvir-ritonavir or Molnupiravir. It reinforces that both antiviral treatments can be used safely regarding the risk of interstitial lung disease in patients with pre-existing autoimmune conditions, addressing an important gap in the literature. How this study might affect research, practice, or policy The findings could influence clinical guidelines and policy decisions regarding the management of COVID-19 in patients with autoimmune diseases, suggesting that healthcare providers can use either nirmatrelvir-ritonavir or Molnupiravir without an increased risk of interstitial lung disease . This study might prompt further research into the long-term effects of COVID-19 treatments on different subpopulations, particularly those with chronic underlying conditions. Policymakers might consider these results when developing targeted recommendations for COVID-19 treatment in populations at increased risk for severe outcomes.