Brain metastases (BMs) frequently involve infratentorial regions, yet the clinical implications of metastases in these areas remain unclear. In this retrospective analysis, 1102 patients with a total of 4365 BM lesions were examined. MRI scans were processed using voxel-wise mapping to create normalized tumor frequency heatmaps, and Analysis of Differential Involvement (ADIFFI) identified clusters with statistical significance. Survival outcomes were evaluated using Kaplan-Meier analysis and Cox proportional hazards models. High relative risk of metastasis was observed in the parietal, insular, left occipital lobes, and cerebellum. Site-specific patterns were evident, with lung, breast, and colorectal cancer BMs frequently affecting infratentorial regions, while melanoma BMs were less common in these locations. Significant infratentorial clusters were associated with younger patients, male sex, lung neuroendocrine and squamous cell carcinomas, elevated Ki-67 expression, and poorer clinical outcomes. Patients with three or more BMs and those receiving whole-brain radiotherapy alone had worse overall survival. In patients undergoing surgical treatment, infratentorial BM involvement was an independent predictor of poor prognosis (p = 0.023; hazard ratio = 1.473; 95% CI: 1.055–2.058). These results improve understanding of BM spatial patterns and offer guidance for diagnosis, treatment strategies, and prognostic evaluation.
