Safe and effective oral therapies for chronic venous insufficiency (CVI) would provide an important alternative to mechanical compression treatment. Several narrative reviews and one systematic review have summarized the efficacy of horse chestnut seed extract (HCSE), but to our knowledge no systematic review has included data from both randomized controlled trials (RCTs) and large-scale observational studies regarding outcomes as well as adverse events.Using a systematic literature search, we identified 13 RCTs of CVI (1,051 patients) and 3 observational studies (10,725 patients) that met our inclusion criteria. Examined outcomes were leg volume, ankle and calf circumference, edema, pain, sensation of tension, swelling, leg fatigue/heaviness, calf cramps, and itching. Random and fixed effect models were used to pool outcomes and adverse events separately for RCTs and observational studies.Overall, the RCTs indicated that HCSE improved symptoms in patients with CVI. Compared to placebo, HCSE reduced leg volume by 46.4 ml (95% CI, 11.3-81.4 ml) and increased the likelihood of improvement in leg pain 4.1-fold (95% CI, 0.98-16.8). Similarly, improvement probabilities were increased 1.5-fold (95% CI, 1.2-1.9) for edema and 1.7-fold (95% CI, 0.01-3.0) for itching. There was insufficient evidence to demonstrate HCSE's effect on leg fatigue/heaviness or calf cramps. Observational studies showed significant effectiveness regarding pain, edema, and leg fatigue/heaviness. No severe adverse events were reported, and HCSE did not significantly increase mild adverse events.Based on meta-analyses of RCTs and observational studies, HCSE appears to be an effective and safe treatment for CVI. Further RCTs and carefully conducted large-scale observational studies are required to evaluate the long-term effectiveness and safety of HCSE in routine settings.