We aimed to explore the efficacy and safety of ultrasound-guided foam sclerotherapy combined with endoluminal radiofrequency closure in patients with varicose veins of lower extremities (VVLEs); furthermore, we aimed to provide a theoretical basis for the effective management of VVLE patients in clinical work. From January 1, 2020, to March 1, 2021, 88 patients with VVLE admitted to Third Hospital of Shandong Province were included in this retrospective study. Depending on the type of treatment, the patients were divided into study groups and control groups. The study group consisted of 44 patients who were given ultrasound-guided foam sclerotherapy combined with endoluminal radiofrequency closure. The control group consisted of 44 patients who were given high ligation and stripping of the great saphenous vein. Efficacy indicators included postoperative venous clinical severity score (VCSS) of affected limb and postoperative visual analogue scale (VAS) score. Safety indicators included length of operation, intraoperative blood loss, length of postoperative rest in bed, length of hospital stay, postoperative heart rate, preoperative blood saturation (SpO2 ), preoperative mean arterial pressure (MAP), and complications. The VCSS score 6months after operation in the study group was significantly lower than that in the control group (P < .05). The pain VAS score in the study group was significantly lower than that in the control group at 1 and 3 days after operation (both P < .05). Compared with the control group, the study group was significantly lower in length of operation, intraoperative blood loss, postoperative in-bed time, and hospital stays (all P < .05). Heart rate and SpO2 were significantly higher, and MAP was significantly lower in the study group compared with that in the control group 12 hours after surgery (all P < .05). The overall postoperative complication rate in the study group was significantly lower than that in the control group (P < .05). In conclusion, compared with surgical treatment of high ligation and stripping of the great saphenous vein, ultrasound-guided foam sclerotherapy combined with endoluminal radiofrequency ablation for the treatment of VVLE disease has better efficacy and safety, which is worthy of clinical promotion.