OBJECTIVE Stereotactic radiosurgery (SRS) is the primary modality for treating brain metastases. However, effective radiosurgical control of brain metastases ≥ 2 cm in maximum diameter remains challenging and is associated with suboptimal local control (LC) rates of 37%-62% and an increased risk of treatment-related toxicity. To enhance LC while limiting adverse effects (AEs) of radiation in these patients, a dose-dense treatment regimen using 2-staged SRS (2-SSRS) was used. The objective of this study was to evaluate the efficacy and toxicity of this treatment strategy. METHODS Fifty-four patients (with 63 brain metastases ≥ 2 cm) treated with 2-SSRS were evaluated as part of an institutional review board-approved retrospective review. Volumetric measurements at first-stage stereotactic radiosurgery (first SSRS) and second-stage SRS (second SSRS) treatments and on follow-up imaging studies were determined. In addition to patient demographic data and tumor characteristics, the study evaluated 3 primary outcomes: 1) response at first follow-up MRI, 2) time to local progression (TTP), and 3) overall survival (OS) with 2-SSRS. Response was analyzed using methods for binary data, TTP was analyzed using competing-risks methods to account for patients who died without disease progression, and OS was analyzed using conventional time-to-event methods. When needed, analyses accounted for multiple lesions in the same patient. RESULTS Among 54 patients, 46 (85%) had 1 brain metastasis treated with 2-SSRS, 7 patients (13%) had 2 brain metastases concurrently treated with 2-SSRS, and 1 patient underwent 2-SSRS for 3 concurrent brain metastases ≥ 2 cm. The median age was 63 years (range 23-83 years), 23 patients (43%) had non-small cell lung cancer, and 14 patients (26%) had radioresistant tumors (renal or melanoma). The median doses at first and second SSRS were 15 Gy (range 12-18 Gy) and 15 Gy (range 12-15 Gy), respectively. The median duration between stages was 34 days, and median tumor volumes at the first and second SSRS were 10.5 cm (range 2.4-31.3 cm) and 7.0 cm (range 1.0-29.7 cm). Three-month follow-up imaging results were available for 43 lesions; the median volume was 4.0 cm (range 0.1-23.1 cm). The median change in volume compared with baseline was a decrease of 54.9% (range -98.2% to 66.1%; p < 0.001). Overall, 9 lesions (14.3%) demonstrated local progression, with a median of 5.2 months (range 1.3-7.4 months), and 7 (11.1%) demonstrated AEs (6.4% Grade 1 and 2 toxicity; 4.8% Grade 3). The estimated cumulative incidence of local progression at 6 months was 12% ± 4%, corresponding to an LC rate of 88%. Shorter TTP was associated with greater tumor volume at baseline (p = 0.01) and smaller absolute (p = 0.006) and relative (p = 0.05) decreases in tumor volume from baseline to second SSRS. Estimated OS rates at 6 and 12 months were 65% ± 7% and 49% ± 8%, respectively. CONCLUSIONS 2-SSRS is an effective treatment modality that resulted in significant reduction of brain metastases ≥ 2 cm, with excellent 3-month (95%) and 6-month (88%) LC rates and an overall AE rate of 11%. Prospective studies with larger cohorts and longer follow-up are necessary to assess the durability and toxicities of 2-SSRS.