Background: Successful treatment of influenza depends on an accurate diagnosis of the illness and prompt intervention. However, there is a lack of data comparing clinical diagnosis vs laboratory diagnostic techniques. Objective: To compare the clinical diagnosis of community cases of influenza with various laboratory diagnostic techniques including multiplex, reverse transcription polymerase chain reaction. Methods: Clinical diagnosis, viral isolation, hemagglutinin inhibition serology, and multiplex, reverse transcription polymerase chain reaction were used to diagnose influenza in patients enrolled in international phase 3 studies designed to investigate the efficacy and safety of an anti-influenza drug (inhaled zanamivir). Patients clinically diagnosed with influenza were enrolled at centers across North America and Europe. Results: A total of 791 (77%) of 1033 patients with laboratory results from all 3 methods were confirmed positive for influenza by 1 or more test results. For 692 patients (67%), the results of all 3 tests agreed. Total symptom scores at baseline showed a significant association toward greater severity of symptoms with an increasing number of positive test results (P<.001). An increasing number of positive test results also showed a significant correlation with a longer time to alleviation of symptoms of influenza in the placebo group (P=.001). Conclusions: During a time when influenza was known to be circulating and clinical diagnostic criteria were applied, diagnosis of influenza in these trials was accurate in approximately 77% of adults on clinical grounds alone. This highlights the need for primary care physicians to be alerted to circulating influenza and to be aware that presentation with cough and fever provide the most predictive symptoms.