OBJECTIVE The aim of this study was to analyze the early radiological response of melanoma brain metastases to single high-dose irradiation and to reveal possible correlations between tumor radioresponsiveness and patient clinical outcomes. METHODS The authors performed a retrospective analysis of the medical data for all patients with melanoma brain metastases who had undergone Gamma Knife radiosurgery (GKRS) and follow-up MRI examinations with standard protocols at regular 2- to 3-month intervals. Volumetric measurements of the metastases on pretreatment and initial posttreatment images were performed to assess the rate of early radiological response. Patients were divided into 2 groups according to the rate of response, and overall survival, local control, and the appearance of new metastases in the brain were compared in these groups using the long-rank test. Univariate and multivariate analyses were performed to identify predictors of clinical outcomes. RESULTS After retrospective analysis of 298 melanoma brain metastases in 78 patients, the authors determined that early radiological responses of these metastases to GKRS differ considerably and can be divided into 2 distinct groups. One group of tumors underwent rapid shrinkage after radiosurgery, whereas the other showed minor fluctuations in size (rapid- and slow-response groups, respectively). Median survival for patients with a slow response was 15.2 months compared with 6.3 months for those with a rapid response (p < 0.0001). In the multivariate analysis, improved overall survival was associated with a slow response to radiosurgery (p < 0.0001), stable systemic disease (p = 0.001), and a higher Karnofsky Performance Scale score (p = 0.001). Stratification by Recursive Partitioning Analysis, score index for radiosurgery, and diagnosis-specific Graded Prognostic Assessment classes further confirmed the difference in overall survival for patients with a slow versus rapid radiation response. Local recurrence was observed in 11% of patients with a rapid response and in 6% of patients with a slow response, at a median of more than 8 months after radiosurgery. New brain metastases were diagnosed in 67% of patients with a slow response at a median of 8.6 months after radiosurgery and in 82% of patients with a rapid response at a considerably earlier median time of 2.7 months. In the multivariate analysis, a longer time to the development of new brain metastases was associated with a slow response (p = 0.012), stable systemic disease (p = 0.034), and a single brain metastasis (p = 0.030). CONCLUSIONS Melanoma brain metastases show different early radioresponsiveness to radiosurgery. Rapid shrinkage of brain metastases is associated with poor patient prognosis, which may indicate more aggressive biological behavior of this tumor phenotype.