Background: Respiratory tract infections (RTIs) is the highest prevalent disease and southern china has a wide spectrum of respiratory pathogen. The aim of this work was to renew the epidemiology characteristics of respiratory pathogens found in children and adults with RTIs from 2018 to 2020 in southern China. Methods: In this work, a total of 134,552 nasopharyngeal or throat swabs (patients from 407 hospitals) were analyzed, and fourteen respiratory viruses (Influenza A virus, influenza B virus, parainfluenza viruses, respiratory syncytial virus, adenovirus, human rhinovirus, human metapneumovirus, human Coronavirus, human bocavirus, enterovirus, cytomegalovirus, herpes simplex virus, mycoplasma pneumoniae and chlamydia pneumoniae) were detected using PCR/RT-PCR. Result: The most common respiratory pathogens in southern china were ADV (16.19%), RSV (15.48%), RHV (11.51%), IAV (10.93%), MP (8.95%), EBV (8.70%), PIV (7.67%), IBV (5.44%), with IAV and ADV as the most prevalent pathogens in adults (11.68%) and children (17.10%) respectively. In detail, ADV (16.30%) and RSV (18.93%) are most common in 0-4 years old, with IAV (16.68%), ADV (20.36%) in 5-14 years old, with EBV (7.48%, 8.74%), IAV (15.43, 9.76%) in 15-49y, 50-64y and IAV (7.37%), IBV (2.43%) in 65-105y. Over three years witnessed an increase in PDR of PIV in 0-4y, 5-14y and 65-105y, and RHV in 5-14y and 15-49y. In month distribution, the positive detection rate of pathogens in adults were generally lower than that in children except for EBV and majority of pathogens has shown a sharp decline in 2020. In Upper RTIs, 77.27% (17/ 22) of co-infected patients had infection to ADV, with poly-infection to ADV and RHV the highest (8/22). In Lower RTIs, the ADV infected patients showed that its co-infection rate to MP, PIV, RHV or RSV were 19.51% (48/246), 15.45% (38/246), 14.63% (36/246) and 14.63% (36/246) respectively. Only IAV, IBV and EBV were detected in co-infection patients with lower RTIs. Conclusion: IAV and ADV were the most important respiratory pathogen in adults and children respectively in southern Chin and cross-reactivity might exist between ADV, RHV, PIV and MP. These should be taken into consideration when they formulate the strategies for co-infection avoidance in patients.