OBJECTIVES: The aim of this study was to estimate the impact on HRQL of in- and outpatients with confirmed Influenza A H1N1/2009, and estimate the associated burden during the pandemic season 2009-2010. METHODS: Longitudinal, observational, multi-centre study of in- and outpatients with confirmed diagnosis of influenza A H1N1/2009 in Spain. Baseline sociodemographic and clinical characteristics and HRQL were assessed at the hospitalization or primary care visit recruitment. HRQL in the previous 7 days was also assessed. A sub-sample of patients was followed-up after recovery. The EQ-5D was used to describe HRQL and calculate utilities. HRQL loss was evaluated among in- and outpatients by several characteristics. Loss of Quality Adjusted Life Years (QALYs) was calculated at individual level taking into account the length of the influenza syndrome. Global burden was estimated from the total number of cases in Spain. RESULTS: A total of 432 inpatients and 563 outpatients were included and 145 and 184, respectively, were followed-up. EQ-5D index previous to influenza was 0.81 (CI95% 0.78–0.84) for inpatients and 0.93 (CI95% 0.91–0.94) for outpatients. During influenza, HRQL loss was -0.58(0.02) for inpatients, and -0.43(0.02) for outpatients. For all patients, Pain/discomfort and Usual Activities were the most affected dimensions presenting a deterioration from 73% to 80%. The individual QALYs loss for inpatients was 0.0135 and for outpatients, 0.0098. In contrasts, the global burden was 41 (inpatients) and 7,283 QALYs (outpatients). CONCLUSIONS: Influenza H1N1/2009 supposed a significant, but transient, impact on patients HRQL. The pandemic produced a considerable QALYs loss, especially among less severe patients, comparable with the burden of some chronic diseases and higher than that of other infectious diseases.