The aim of this independent study was to evaluate the protective effects, on the development of flight edema, of Venoruton. The study included patients with venous disease traveling in economy in long-haul flights (9 hours). Edema is a relevant aspect of long-haul flights affecting both patients with venous disease and normal subjects. Microcirculatory variations during flights cause a microangiopathy and biochemical and coagulation alterations. This condition may be defined as flight microangiopathy. A group of 203 subjects with chronic venous disease (uncomplicated varicose veins) at low-medium risk for DVT were contacted; 43 subjects were excluded for several nonmedical, travel-related problems or inconvenient evaluation time; the remaining 160 were randomized, after informed consent, into 2 groups to evaluate 2 prophylaxes in 7-8-hour, long-haul flights: The treatment group received Venoruton (hydroxyethyl rutosides) 1 g twice daily for 3 days (2 days before the flight and the day of the flight). The control group received comparable placebo. The edema score was based on the edema tester, ankle circumference, volume measurements, subjective swelling, and discomfort score. Items 1, 4, and 5 are based on an analogue scale line (1 to 10) directly defined by the subjects before and after the flights. Of the 160 included subjects 139 completed the study. Dropouts (21) were due to poor compliance, traveling, and/or connection problems (11 in the control group, 10 in the treatment group). Age and sex distribution were comparable in the 2 groups as were risk factors distributions. The level of edema at inclusion was comparable in the 2 groups of subjects. After the flight there was an average score of 7.2 (sd 2) in the control group, while in the Venoruton group the score was on average 3.2. (sd 1.1) (p < 0.05), 2.25 times lower than in the control group (p < 0.05). In the control group 89% of the subjects had an evident increase in ankle circumference and volume, which was clearly visible at inspection and associated with discomfort. In the Venoruton group edema was clearly present in 12% of subjects (associated with discomfort between 5 and 7 on the analogue scale line) and it was mild-moderate, not associated with symptoms (pain, discomfort between 2 and 4 on the analogue scale line). Therefore, the control of flight edema with Venoruton was clear both considering parametric data (circumference and volume) and nonparametric (analogue scale lines) measurements. The combined evaluation of the edema score is significantly favorable for patients treated with Venoruton. No deep vein thrombosis or superficial vein thrombosis was observed in this study.