The efficacy of viscosupplementation for the relief of pain and disability caused by knee osteoarthritis has been demonstrated, but its effects on Quality of Life (QoL) are less well known. The aim of this study was to describe the changes in QoL in patients receiving hylane G-F 20 in routine practice for the treatment of knee osteoarthritis and to determine the factors associated with changes in QoL. An observational, prospective, multicentre study was carried out in private ambulatory care patients. The study population consisted of patients receiving hylane G-F 20 injections for symptomatic, radiological Kellgren stage II or III knee osteoarthritis. The clinical and demographic data were recorded at inclusion and the QoL, SF36 and OsteoArthritis Knee and Hip Quality Of Life (OAKHQOL) questionnaires administered before the first injection and then during the 3- and 6-month visits. Three hundred patients were enrolled in the study (61% female, mean age 67 ± 11 years, 45% Kellgren stage II). After 3 and 6 months, all the SF36 scores and three OAKHQOL scores had significantly improved. In the multivariate analysis, low QoL scores at inclusion were correlated with a more marked improvement (p < 0.0001). Prior treatment with a viscosupplement was associated with a less substantial improvement in the SF36 physical functioning (β = 11.2, p = 0.03) and OAKHQOL mental health scores (β = 9.1, p = 0.01). The presence of effusion was only associated with changes on the SF36 physical functioning score (β = 15.4, p = 0.005). Administered in routine practice for symptomatic knee osteoarthritis, hylane G-F 20 improves QoL. Both joint effusion and prior viscosupplementation could be associated with a more modest improvement in QoL.