Chronic venous insufficiency (CVI) results in considerable morbidity and may seriously affect patients' quality of life. The RELIEF (Reflux assEssment and quaLity of life improvEment with micronized Flavonoids) Study was a prospective controlled study designed to assess differences in the severity and in the evolution of symptoms and signs of CVI according to presence or not of venous reflux. Patients were thus separated into 2 comparative groups: those presenting venous reflux and those without venous reflux. The design of the study was multicentric and international, carried out in 23 countries over 2 years, in which 5,052 symptomatic patients assigned to classes C0 to C4 (on the basis of CEAP clinical classification) were enrolled. Patients were treated with micronized purified flavonoid fraction (MPFF), consisting of 450 mg of micronized diosmin and 50 mg of flavonoids expressed in hesperidin over 6 months. In order to document changes in the quality of life of these patients during MPFF treatment, a new validated Quality of Life Questionnaire specific to CVI (CIVIQ) was used. The study also set out to gather epidemiologic data including the prevalence of venous reflux in symptomatic patients. The RELIEF study provided important information about the epidemiology and clinical manifestations of CVI. Of particular interest was the observation that venous reflux was found to be absent in 57% of patients diagnosed as suffering from CVI belonging to CEAP classes C0 to C4. A positive relationship between symptoms of CVI (pain, leg heaviness, sensation of swelling, and cramps) and presence of venous reflux was found in the RELIEF study: symptoms were more frequent and more severe at presentation in patients with venous reflux. Moreover, during MPFF treatment, all symptoms showed a greater decrease in the group without venous reflux compared with the other group. This difference in the evolution of symptoms between the 2 groups was significant for pain, sensation of swelling, and cramps. Regarding leg heaviness and signs such as edema (assessed by leg circumference), patients improved equally independently of the presence or not of venous reflux. The significant and progressive improvement in the signs of CVI was reflected in significant changes in the clinical class of the CEAP classification, ie, from more severe to less severe stages. Continuous clinical improvement was found throughout the study and after treatment with MPFF for 6 months, the clinical scores of all symptoms and signs had significantly decreased (p=0.0001 versus DO) in both groups. This improvement was also associated with a significant and continuous progression in the quality of life scores of all patients. Age of patients, average time since diagnosis, and presence of venous reflux increased with the severity of the disease. The relationship shown in this study between these parameters and clinical CEAP classification reflects the progressive nature of CVI. Despite obvious symptoms of CVI, a very low percentage (21.8%) of the "intention-to-treat" (ITT) population had previously been treated. This was the case whether venous reflux was present or not.