Background: The Northern Hemisphere faces the prospect of the coronavirus disease 2019 (COVID-19) pandemic and a simultaneous epidemic of seasonal influenza. However, the clinical impacts of single and dual infections with influenza A (H1N1) and SARS-CoV-2 haven’t been well described. Objectives: We aim to compare the clinical features, severity and outcome among patients with single and dual infections with influenza A (H1N1) and SARS-CoV-2. Methods: Characteristics and outcomes in adults (≥18 years) hospitalized for H1N1 infection (n = 220) were retrospectively compared with cases hospitalized for SARS-CoV-2 infection (n = 249) and co-infection with both viruses (n = 36) in a single-center study in Guangzhou, China. Results: Compared with COVID-19 infection, patients with H1N1 were more likely to have clinical symptoms (P < 0.05), higher admission body temperature (37.8 vs 37.2℃, P < 0.05), but shorter duration of hospitalization (7.0 vs 17.5 days, P < 0.05) and lower incidence of pneumonia during hospitalization (46.8% vs 73.1%, P < 0.05). Co-infection tended to be more common among older patients (median age 56.0 years old) and was associated with increased odds of prolonged duration of hospitalization (>20 d), pneumonia, secondary bacterial infections and admittance to ICU, compared with H1N1 patients (P < 0.05). Conclusion: COVID-19 patients have a higher incidence of pneumonia during hospitalization whilst fewer onset symptoms than H1N1 patients. Co-infection was more found in older age and was associated with poorer clinical outcomes.