BACKGROUND AND OBJECTIVES: Brain metastases (BM) develop in nearly half of the patients with advanced melanoma. The aim of this retrospective historical cohort study was to analyze radiological response of melanoma BM to single-fraction Gamma Knife radiosurgery (GKRS), in relation to biologically effective dose (BED) for various alpha/beta ratios. METHODS: Included in the study were 274 lesions. Primary outcome was local control (LC). Mean marginal dose was 21.6 Gy (median 22, range 15-25). Biologically effective dose was calculated for an alpha/beta ratio of 3 (Gy(3)), 5 (Gy(10)), 10(Gy(10)), and 15 (Gy(15)). RESULTS: Receiver operating characteristic value for LC and BED was 85% (most statistically significant odds ratio 1.14 for BED Gy(15), P= .006), while for LC and physical dose was 79% (P = .02). When comparing equality of 2 receiver operating characteristic areas, this was statistically significant (P = .02 and .03). Fractional polynomial regression revealed BED (Gy(10 )and Gy(15)) as statistically significant (P = .05) with BED of more than 63 Gy(10) or 49 Gy(15) as relevant, also for higher probability of quick decrease in volume first month after GKRS and lower probability of radiation necrosis. Shorter irradiation time was associated with better LC ( P= .001), particularly less than 40 minutes (LC below 90%, P = .05). CONCLUSION: BED Gy(10) and particularly Gy(15) were more statistically significant than physical dose for LC after GKRS for radioresistant melanoma BM. Irradiation time (per lesion) longer than 40 minutes was predictive for lower rates of LC. Such results need to be validated in larger cohorts