The purpose of this study is to compare the safety and efficacy of single fraction radiosurgery (SFR) with hypofractionated radiosurgery (HR) for the adjuvant treatment of large, surgically resected brain metastases. Seventy-five patients with 76 resection cavities ≥ 3 cm received 15 Gray (Gy) × 1 SFR (n = 40) or 5-8 Gy × 3-5 HR (n = 36). Cumulative incidence of local failure (LF) and radiation necrosis (RN) was estimated accounting for death as a competing risk and compared with Gray's test. The effect of multiple covariates was evaluated with the Fine-Gray proportional hazards model. The most common HR dose-fractionation schedules were 6 Gy × 5 (44%), 7-8 Gy × 3 (36%), and 6 Gy × 4 (8%). The median follow-up was 11 months (range 2-71). HR patients had larger median resection cavity volumes (24.0 vs. 13.3 cc, p < 0.001), planning target volumes (PTV) (37.7 vs. 20.5 cc, p < 0.001), and cavity to PTV expansion margins (2 vs. 1.5 mm, p = 0.002) than SFR patients. Cumulative incidence of LF (95% CI) at 6 and 12-months for HR versus SFR was 18.9% (0.07-0.34) versus 15.9% (0.06-0.29), and 25.6% (0.12-0.42) versus 27.2% (0.14-0.42), p = 0.80. Cumulative incidence of RN (95% CI) at 6 and 12 months for HR vs. SFR was 3.3% (0.00-0.15) versus 10.7% (0.03-0.23), and 10.3% (0.02-0.25) versus 19.2% (0.08-0.34), p = 0.28. On multivariable analysis, SFR was significantly associated with an increased risk of RN, with a HR of 3.81 (95% CI 1.04-13.93, p = 0.043). Hypofractionated radiosurgery may be the more favorable treatment approach for radiosurgery of cavities 3-4 cm in size and greater.