Abstract： Background::Extra-corporeal video telescope operating monitor system provides a necessary instrument to perform high-precision neurosurgical procedures that could substitute or supplement the traditional surgical microscope. The present study was designed to evaluate a compact high-definition two-dimensional exoscope system for assisting in surgical removal of large vestibular schwannoma (VS), as an alternative to a binocular surgical microscope.Methods::Patients with Koos grade 3 and grade 4 VS undergoing surgery were enrolled in this prospective cohort study between January 2013 and June 2018. The demographics and tumor characteristics (size, Koos grade, composition [cystic or solid mass]) were matched between the two groups of patients. The following outcome measurements were compared between the two groups: duration of surgery, volume of blood loss, extent of tumor resection, number of operating field adjustments, pre- and post-operative facial and cochlear nerve function evaluated at 3 months post-surgery, complications and surgeons’ comfortability.Results::A total of 81 patients received tumor resection through the retrosigmoid approach under either an exoscope (cases, n = 39) or a surgical microscope (control, n = 42). Patients in the two groups had comparable tumor location ( P = 0.439), Koos grading ( P = 0.867), and composition ( P = 0.891). While no significant differences in the duration of surgery ( P = 0.172), extent of tumor resection ( P = 0.858), facial function ( P = 0.838), and hearing ability ( P = 1.000), patients operated on under an exoscope had less blood loss ( P = 0.036) and a fewer field adjustments ( P < 0.001). Both primary and assistant surgeons reported a high level of comfort operating under the exoscope ( P = 0.001 and P < 0.001, respectively). Conclusions::The compact high-definition two-dimensional exoscope system provides a safe and efficient means to assist in removing large VSs, as compared to a surgical microscope. After the acquaintance with a visual perception through a dynamic hint and stereoscopically viewing corresponding to the motion parallax, the exoscope system provided a comfortable, high-resolution visualization without compromising operational efficiency and patient safety.