As a noninvasive treatment technique, ultrasound-guided high-intensity focused ultrasound (HIFU) has been considered as a routine treatment for uterine fibroids and adenomyosis in China. Contrast-enhanced ultrasound (CEUS) has been proposed as another option to assess the treatment efficacy during HIFU treatment. The aim of this investigation is to evaluate the adverse effects of HIFU ablation for benign uterine diseases in a group of patients studied with ultrasound contrast agent (UCA), in comparison with a group of patients not exposed to UCA. From November 2010 to December 2013, 2604 patients with benign uterine diseases were treated with HIFU. Among them, 1300 patients were exposed to an UCA, whereas 1304 patients were not.During HIFU procedure, the incidences of leg pain, sacral/buttock pain, groin pain, treatment area pain, and the discomfort "hot" sensation on skin were higher in the patients who were exposed to SonoVue (Bracco, Milan, Italy) than those who were not (20.5% vs 11.7%, 52.5% vs 42.3%, 6.5% vs 4.5%, 68.9% vs 55.4%, and 48.1% vs 42.9%, respectively). Among the postoperative adverse effects, the incidence of lower abdominal pain was significantly higher in patients who were exposed to an UCA than those who were not (51.2% vs 39.9%, P < 0.05). Two patients who were exposed to an UCA had acute renal function failure.In conclusion, UCA may increase the incidences of some common HIFU-related adverse effects during HIFU treatment for benign uterine diseases, but most of which were acceptable and self-limited. After HIFU treatment, renal function should be monitored in patients with a history of hypertension or taking nonsteroidal anti-inflammatory drugs.