Comparisons of the clinical characteristics of contemporaneous pandemic (H1N1) 2009 influenza A virus (A(H1N1)pdm09)- and seasonal influenza viruses-infected patients are important for both clinical management and epidemiological studies. A prospective multicenter observational study was conducted using a preestablished sentinel surveillance system in Guangzhou, China during 2009. In this study, the clinical presentations of patients with either acute respiratory infection or community-acquired pneumonia were recorded, and nasopharyngeal swab samples were collected for detection of respiratory virus strains using cell cultures or real-time reverse transcription/real-time polymerase chain reaction. Comparisons of the clinical features between A(H1N1)pdm09- and seasonal influenza viruses-infected patients were conducted accordingly. Of the 1,498 patients examined, 265 tested positive for A(H1N1)pdm09, 286 were positive for seasonal influenza A viruses, and 137 for influenza B viruses. The predominant virus was influenza B before the emergence of A(H1N1)pdm09 (epidemiological week [EW] 1-EW 21); then, predominantly non-A(H1N1)pdm09 influenza A and, later, A(H1N1)pdm09, which peaked in EW 46. Compared with the common seasonal influenza-infected patients, A(H1N1)pdm09-infected patients were younger, and had a higher proportion of these patients reported prior contact with infected individuals (P < 0.001, by χ(2) test). However, few significant differences were observed in clinical symptoms and severity among any of the infections caused by the different influenza A strains. Our hospital-based network served as a useful source of information during A(H1N1)pdm09 monitoring. Viral distribution in Guangzhou was characterized by a sharp rise in A(H1N1)pdm09-infected patients in September 2009. Similar to seasonal influenza A-infected cases, A(H1N1)pdm09 cases had a very small proportion of severe cases.