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Background: There is little evidence about the relationship between aetiology, illness severity, and clinical course of respiratory tract infections (RTIs) in primary care. Understanding these associations would aid in the development of effective management strategies for these infections., Aim: To investigate whether clinical presentation and illness course differ between RTIs where a viral pathogen was detected and those where a potential bacterial pathogen was found., Design and Setting: Post hoc analysis of data from a pragmatic randomised trial on the effects of oseltamivir in patients with flu-like illness in primary care ( n = 3266) in 15 European countries., Method: Patient characteristics and their signs and symptoms of disease were registered at baseline. Nasopharyngeal (adults) or nasal and pharyngeal (children) swabs were taken for polymerase chain reaction analysis. Patients were followed up until 28 days after inclusion. Regression models and Kaplan-Meier curves were used to analyse the relationship between aetiology, clinical presentation at baseline, and course of disease including complications., Results: Except for a less prominent congested nose (odds ratio [OR] 0.55, 95% confidence interval [CI] = 0.35 to 0.86) and acute cough (OR 0.42, 95% CI = 0.27 to 0.65) in patients with flu-like illness in whom a possible bacterial pathogen was isolated, there were no clear clinical differences in presentations between those with a possible bacterial aetiology compared with those with a viral aetiology. Also, course of disease and complications were not related to aetiology., Conclusion: Given current available microbiological tests and antimicrobial treatments, and outside pandemics such as COVID-19, microbiological testing in primary care patients with flu-like illness seems to have limited value. A wait-and-see policy in most of these patients with flu-like illness seems the best option., (© The Authors.)