OBJECTIVES: Influenza clinical trials usually focus on outcomes such laboratory confirmed infection using viral culture and/or rise in antibody titers to influenza antigens. However, new agents are not only expected to reduce infection but infection intensity. Symptom severity and duration symptoms such as fever, cough, malaise, functional impact, and time to return to daily activities have increased importance. The aim was to develop and validate a Patient Reported Outcomes (PRO) measure of the intensity and impact of influenza infection. METHODS: Consistent with US Food and Drug Administration guidelines, construct and item generation were guided by the literature and consultation with patients and expert physicians through concept mapping, focus groups, and interviews. Items were administered to 311 people with influenza like illness (ILI) across 25 USA sites with random assignment to paper or electronic interactive voice response system (IVRS). Analyses included classical psychometrics, structural equation modeling (SEM) and Rasch analyses. RESULTS: A total of 149 concepts covering the influenza experience were derived from concept mapping and these clustered into Symptoms and Impact on Daily activities, Emotions and Others. Impact scales were unidimensional whereas the symptoms domain factored into Systemic and Respiratory symptoms. All domains displayed good internal consistency (Cronbach α≥0.8) except the 3-item Respiratory domain (α=0.48). A six-factor SEM indicated excellent fit where Systemic, Respiratory and Daily activities domains differentiated patients with ILI or confirmed influenza. All scales were responsive over time. SEM indicated paper and IVRS data could be pooled. CONCLUSIONS: The use of FDA-recommended procedures for patient and clinician consultation, robust psychometrics, and evaluation of the items and domains in the target population, has generated rigorous data to support the validity of the FluiiQ. The FluiiQ should improve evaluation of existing and future agents designed to prevent or control influenza infection by increasing the breadth and depth of measurement in this field.