Patients suffering from any class of the Clinical, Etiological, Anatomical, Pathophysiological (CEAP) classification of chronic venous disease (CVD) may be symptomatic (C0s-C6s). Leg heaviness, discomfort, itching, cramps, pain, paresthesia, and edema (C3) are the most frequent manifestations of CVD and a major reason for medical consultation. Daflon 500 mg (micronized purified flavonoid fraction [MPFF]) is an effective treatment for symptoms and edema in CVD as demonstrated in several randomized controlled studies. A 2-month, double-blind study in 40 patients established the superiority of Daflon 500 mg over placebo with regard to symptoms and objective signs. This was confirmed in another double-blind, placebo-controlled trial (2 months' treatment, 160 patients), and in the Reflux assEssment and quaLity of lIfe improvEment with micronized Flavonoids (RELIEF) study. The latter included 5,052 patients in 23 countries, using a visual analog scale for evaluating pain, leg heaviness, cramps, and a sensation of swelling. All symptoms showed significant and progressive improvement. The quality-of-life results (scores on the ChronIc Venous Insufficiency quality of life Questionnaire [CIVIQ]) paralleled those of symptoms. The decrease in the ankle and calf circumferences was significantly greater (p < 0.001) in the group of patients treated with Daflon 500 mg in two studies, and correlated well with the improvement in the sensation of swelling (p < 0.001). This was confirmed with more sophisticated measurement techniques as in the RELIEF study or in a trial assessing edema with an optoelectronic volumeter in 20 patients. A further double-blind, randomized, controlled study established a statistically significant difference in favor of Daflon 500 mg in comparison with diosmin, both on symptoms and edema. The therapeutic efficacy of Daflon 500 mg on CVD symptoms and edema has been demonstrated in double-blind, randomized, controlled studies. Further studies using a new approach may define the most precise and validated methodology for application in future research in phlebology.