Objective To show the superiority of 500 mg calcium dobesilate vs. placebo in reduction of edema of the lower limbs in patients with chronic venous insufficiency, Clinical, Etiological, Anatomical and Pathophysiological classes C3/C4. Methods A total of 351 patients were randomized (n = 174 calcium dobesilate, n = 177 placebo). Active treatment was 500 mg calcium dobesilate, three times daily for 12 weeks, with a 12-week follow-up. Results At the end of treatment, the relative volume change in the most pathological leg was −0.6 ± 4.8% with calcium dobesilate compared to −0.3 ± 3.3% with placebo (p = 0.09). At the end of follow-up, this was −1.01 ± 5.4% for calcium dobesilate vs. −0.08 ± 3.5% for placebo (p = 0.002). Conclusions Calcium dobesilate treatment resulted in no significant volume change in the most pathological leg between baseline and end of treatment. However, the calcium dobesilate group showed a significantly greater volume decrease in the most pathological leg at the end of follow-up. Calcium dobesilate was well-tolerated, with a safety profile consistent with previously published data.