The present study was designed to compare the safety and efficacy of a combination of Ruscus aculeatus, hesperidin methyl chalcone, and ascorbic acid (Cyclo 3 Fort) versus that of hydroxyethyl rutoside in treatment of chronic venous lymphatic insufficiency. This open-label, randomized multicenter study was conducted on outpatients treated for 90 days. The patients were from three different regions of Argentina. Eighty patients, men and women, 30 to 70 years of age, with symptoms of chronic venous lymphatic insufficiency, ie, heavy, tired, swollen, or painful legs, were enrolled and assigned to two groups: one group treated with Cyclo 3 Fort, the other with rutoside. The symptoms were assessed at baseline, and after 30, 60, and 90 days. The patient was asked to assess subjective symptoms, and the physician measured the size of the affected limbs. The efficacy was rated on a 3-point scale and safety was evaluated by the number of side effects. The results show that when all patients were comparable at baseline, after 90 days, patients treated with Cyclo 3 Fort reported more rapid and complete regression of symptoms than those in the rutoside group, a statistically significant difference (p < 0.01). Likewise, a significant reduction in affected limb size was observed in both groups but persisted after 90 days in the Cyclo 3 Fort group only (p < 0.01). Cyclo 3 Fort was safe and more effective than rutoside in the treatment of venous lymphatic insufficiency, and the Cyclo 3 Fort efficacy is probably associated with its unique mechanism of action.