Background <p>Baricitinib was shown to reduce the mortality of COVID-19 patients, but real world data about baricitinib in combination with nirmatrelvir/ritonavir for the treatment of elderly patients with severe or critical COVID-19 were limited. The aim of the study was to determine the effects and hospital-acquired infections occurrence after combined medication in these patients.</p> Methods <p>We included severe or critical COVID-19 patients treated at Beijing Chaoyang Hospital from December 2022 to February 2023. We investigated duration of hospital stay, factors associated with reduced mortality risk, IL-6 levels and the characteristics of hospital-acquired infections in patients treated with baricitinib with nirmatrelvir/ritonavir.</p> Results <p>The median age of the 117 included patients was 79 (interquartile range [IQR]: 70–85) years. Thirty-six patients received baricitinib with nirmatrelvir/ritonavir, 16 of whom died. The factors associated with reduced mortality were the administration of baricitinib with nirmatrelvir/ritonavir (hazard ratio [HR]: 0.405 (95% CI: 0.183–0.90), <i>p</i> = 0.026)). The IL-6 levels were 0.75 (IQR: 0.55–1.82) log₁₀ pg/mL before or within 2 days of baricitinib administration, and it was 1.45 (IQR: 0.94–2.07) log₁₀ pg/mL after baricitinib administration for 6 to 8 days. A mixed-effects model showed a statistically significant effect of Time on IL-6 levels (F(1, 20.757) = 6.299, <i>p</i> = 0.020). The fixed effects estimates indicated that each one-day increase during the treatment period, IL-6 levels increased by an average of 0.081 units (<i>B</i> = 0.081, <i>SE</i> = 0.032, t (20.757) = 2.510, <i>p</i> = 0.020, 95% CI (0.014, 0.148)). In patients treated with baricitinib, carbapenem-resistant <i>Acinetobacter baumannii</i> (2), carbapenem-resistant <i>Klebsiella pneumoniae</i> (2), and <i>K. pneumoniae</i> (2) were more common pathogens detected in the respiratory tract. Carbapenem-resistant <i>K. pneumoniae</i> (1), <i>Enterococcus faecium</i> (1), and <i>Staphylococcus epidermidis</i> (1) were detected in blood. <i>Enterococcus faecium</i> (2) and <i>K. pneumoniae</i> (1) were identified via urine culture.</p> Conclusion <p>Baricitinib combined with nirmatrelvir/ritonavir was associated with lower mortality in elderly patients with severe or critical COVID-19 in the real world. Carbapenem-resistant <i>A.baumannii</i>and carbapenem-resistant <i>K. pneumoniae </i>were more common pathogens detected in the respiratory tract in these patients.</p> Clinical trial number <p>Not applicable.</p>