| Summary: | The rebound characteristics of respiratory infections after lifting pandemic control measures were uncertain. From January to November 2023, patients presenting at a teaching hospital were tested for common respiratory viruses and <i>Mycoplasma pneumoniae</i> using a combination of antigen, nucleic acid amplification, and targeted next-generation sequencing (tNGS) tests. The number and rate of positive tests per month, clinical and microbiological characteristics were analyzed. A rapid rebound of SARS-CoV-2 was followed by a slower rebound of <i>M. pneumoniae,</i> with an interval of 5 months between their peaks. The hospitalization rate was higher, with infections caused by respiratory viruses compared to <i>M. pneumoniae</i>. Though the pediatric hospitalization rate of respiratory viruses (66.1%) was higher than that of <i>M. pneumoniae</i> (34.0%), the 4094 cases of <i>M. pneumoniae</i> within 6 months posed a huge burden on healthcare services. Multivariate analysis revealed that <i>M. pneumoniae</i>-infected adults had more fatigue, comorbidities, and higher serum C-reactive protein, whereas children had a higher incidence of other respiratory pathogens detected by tNGS or pathogen-specific PCR, fever, and were more likely to be female. A total of 85% of <i>M. pneumoniae</i>-positive specimens had mutations detected at the 23rRNA gene, with 99.7% showing A2063G mutation. Days to defervescence were longer in those not treated by effective antibiotics and those requiring a change in antibiotic treatment. A delayed but significant rebound of <i>M. pneumoniae</i> was observed after the complete relaxation of pandemic control measures. No unusual, unexplained, or unresponsive cases of respiratory infections which warrant further investigation were identified.
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