The vertebral artery (VA)-involved hemifacial spasm (HFS) has distinctive clinical features and performing microvascular decompression (MVD) is challenging. We described the clinical presentations of VA-involved HFS and the outcomes of MVD using the interposition method. Between January 2008 and March 2015, MVD was performed in 271 patients with VA-involved HFS. Demographic characteristics, preoperative severity, intraoperative findings, spasm-free outcome, and complications were retrospectively evaluated. A control group of 1500 consecutive patients with non-VA-involved HFS was enrolled. VA-involved HFS was associated with older age (p < 0.001), less female predominance (p < 0.001), more left-sided predominance (p < 0.001), and rapid symptom progression before MVD (p < 0.001). The Teflon Fulcrum method allowed intraoperative identification of the neurovascular compression site in 92.6% of the cases, and showed more severe indentation on the facial nerve (p < 0.001). Changes in the brainstem auditory evoked potentials during MVD (p < 0.001) and postoperative non-serviceable hearing loss (p < 0.001) were more frequent in patients with VA-involved than in non-VA-involved HFS. The spasm-free outcome and overall complication rates after MVD were not significantly different between the groups. VA-involved HFS has distinctive clinical features and poses a major surgical challenge for MVD success. The interposition method is a feasible surgical strategy in VA-involved HFS.