Purpose: To evaluate and compare the efficacy of corticosteroid and vincristine (VCR) in the treatment of kaposiform hemangioendothelioma (KHE) and tufted angioma (TA). Methods: This was a multicenter prospective randomized controlled study. All patients with KHE/TA who meet the diagnostic criteria were included. The patients were randomized to methylprednisolone (MP) group and VCR group. The primary outcome was the single main parameter effective rate (SMPE) and overall effective rate (OE) of corticosteroid and VCR over one month after treatment. The single main parameters included platelets, fibrinogen, tumor size, texture and appearance. Results: In single main parameters, VCR was superior to corticosteroid in the relief of platelet (80.0% vs 44.0, P = 0.019) and tumor texture (68.9% vs 30.8%, P = 0.007). Although the efficacy of VCR on fibrinogen (23.3% vs 20.7%, P=1.000), tumor size (23.3% vs 13.8%, P=0.273) and appearance (65.5% vs 46.2%, P=0.120) were higher than that of corticosteroid, there was no significant difference (P > 0.05). And the overall effective rate of VCR was higher than that of corticosteroid (31.0% and 56.7% vs 31.0%), but the differences were also not statistically significant. (P=0.067). Conclusions: Our prospective data show that the therapeutic effect of VCR was significantly greater than that of corticosteroid with regard to treating thrombocytopenia and improving tumor texture. So, we recommend that VCR could be an option for first-line treatment in KHE/TA patients.