BACKGROUND CONTEXT: Stereotactic spine radiosurgery (SSRS) shows potentials of better tumor and pain control for limited spinal metastases. However, the optimal schedule of SSRS is not well established and has never been investigated in a prospective randomized trial. PURPOSE: To compare 2 SSRS schedules to determine which results in the lowest rate of grade 3 or higher protocol-specified adverse events at 4 months. STUDY DESIGN: A prospective randomized phase II trial. PATIENT SAMPLE: Patients with biopsy-proven nonhematogenous malignancy and limited unirradiated spine metastases not requiring upfront spine surgery were eligible. Between November 2015 and April 2019, 69 patients were randomly assigned, yielding a total cohort of 63 analyzable patients with 79 treated spinal segments. OUTCOME MEASURES: Primary outcomes were the 4-month grade 3 or higher adverse events determined by the Common Toxicity Criteria for Adverse Events version 4.0 (CTCAE) definitely, probably, or possibly related to single fraction or multiple fractions spine SSRS. METHODS: All patients at a single tertiary medical center who had radiographic evidence of limited spine metastases not requiring upfront spinal surgery were randomized to receive 16 Gy in SF or 24 Gy in 3 fractions. A post-hoc analysis was performed to assess the cumulative incidences and prognostic factors of local progression (LP) and vertebral compression fracture (VCF) by the Fine and Gray competing risk model. RESULTS: Sixty-three patients (29 with 38 spinal segments in the SF arm and 34 with 41 spinal segments in the MF arm) were analyzed. Median follow-up was 16.6 months. At 4 months, none of the patients in the SF arm and 1 patient in the MF arm experienced protocol-specified grade 3 or higher toxicity. The 1-year cumulative incidence of LP was 2.6% for the SF arm and 4.9% for the MF arm, respectively. The 1-year cumulative incidence of VCF was 7.9% and 10.1% for the SF arm and the MF arm, respectively. CONCLUSIONS: Both single-fraction and multifraction SSRS are safe. There was no difference in cumulative incidence of LP or VCF between 2 dose-fractionation schedules. Single-fraction SSRS is more efficient and provides the most acceptable outcome profile for all assessed endpoints.