The aim of this study was to investigate, if the the combined treatment of compression stockings and drug treatment with oxerutins (O-(beta-hydroxyethyl)-rutosides, Venoruton) provides additional benefit for patients with chronic venous insufficiency (CVI) compared to compression treatment alone. Oxerutins belong to the group of oedema protective agents and possess anti-exudative and membrane protective activity. A total of 133 female patients with CVI grade II participated in this double-blind, randomised, multi-centre, parallel-group study with two treatment groups. The whole study lasted for 19 weeks, and consisted of a one week placebo run-in phase, 12 weeks treatment phase, followed by a 6 weeks treatment-free follow-up period. All patients received a basis compression therapy that consisted of standard compression stockings. In order to standardise initial fitting of stockings in this multi-centre setting, stockings were fitted after one week of standard diuretics starting at baseline and then stockings were worn for the following 11 weeks. Patients were randomised to receive oxerutins (2 x 500 mg daily) or matching placebo. Leg volumes (water displacement) and associated subjective symptoms (visula analogue scale) were measured during a placebo run-in period at enrolment (week - 1) and half a week later (week - 1/2), at baseline week 0), at 4, 8, 12 weeks on treatment, and again after a 3- and 6-weeks treatment-free follow-up. The primary efficacy criterion, the area under the baseline from week 0 to week 18 (AUB0-18) of leg volume changes, as measurement of the global change of leg oedema during the study, resulted in a superior reduction of -5589 ml.d for the combined treatment with oxerutins compared to -2101 ml.d for placebo (p = 0.012). The mean change of leg volume compared to baseline after 12 weeks of treatment was -63.9 ml for stockings and oxerutins, and -32.9 ml for the patients who received stockings and placebo (p < 0.05). Oxerutins showed a prolonged effect in the follow-up phase compared to placebo, with mean AUB values for week 12 to week 18 of -1769 ml.d versus -133 ml.d (p < 0.01). The study demonstrated that the combined therapy of compression stockings and drug treatment with oxerutins is significantly superior in reducing leg oedema resulting from chronic venous insufficiency compared to compression treatment alone.